Title of Invention	"A PHARMACEUTICAL COMPOSITION OF HIGH MOLECULAR WEIGHT POLYMERIC DRUGS"
Abstract	The present invention relates to a novel pharmaceutical composition useful for formulating a high molecular weight active(s) in a thixotropic, water swellable, and bioadhesive fill material for dispensing in gelatin and non-gelatin capsule dosage forms. The invention represents the art of formulating pharmaceutically active substances into more elegant medicaments. The present invention is specifically designed for formulating high molecular weight microbicidal agents with intent of providing protection against sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS), by vaginal or rectal route.

Title of Invention

"A PHARMACEUTICAL COMPOSITION OF HIGH MOLECULAR WEIGHT POLYMERIC DRUGS"

Abstract

The present invention relates to a novel pharmaceutical composition useful for formulating a high molecular weight active(s) in a thixotropic, water swellable, and bioadhesive fill material for dispensing in gelatin and non-gelatin capsule dosage forms. The invention represents the art of formulating pharmaceutically active substances into more elegant medicaments. The present invention is specifically designed for formulating high molecular weight microbicidal agents with intent of providing protection against sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS), by vaginal or rectal route.

Full Text	A synergistic pharmaceutical composition for high molecular weight polymer drugs FIELD OF INVENTION The present invention relates to a novel pharmaceutical composition useful for formulating a high molecular weight active(s) in a thixotropic, water swellable, and bioadhesive fill material for dispensing in gelatin and non-gelatin capsule dosage forms. The invention represents the art of formulating pharmaceutically active substances into more elegant medicaments/ The present invention is specifically designed for formulating high molecular weight microbicidal agents with intent of providing protection against sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS), by vaginal or rectal route. But the scope of invention is not limited to the use of microbicides only. The present invention can also be useful for formulating other high molecular weight compounds for vaginal or rectal administration. The art of preparation lies in the fact that the thixotropic capsule fill material is easy to prepare and hydrophobic in nature but when comes in contact with water forms a smooth uniform gel with no visible physical separation of ingredients. The formulation behaves in a thixotropic manner, since it remains flowable at 37°C liquid, which aids in filling into capsules and solidifies at normal room temperature (20-25°C) thus helps in reducing leakage during storage. BACKGROUND OF INVENTION AIDS is a deadly disease causing millions of death each year. Various approaches are used to combat this disease. One such approach being explored extensively for prevention of AIDS is the use of microbicides. Development of microbicides gained impetus in past decade as these compounds not only prevent conception but also provide protection against AIDS. A number of polymeric materials such as sodium cellulose sulfate (Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Andrology 23, 426-438; US patent 6063773), polystyrene sulfonate (Zaneveld LJD, Waller DP, Anderson RA, Chany C, Rcncher VVF, Feathergill K, Diao XH, Doncel GF, Herold B, Cooper M. 2002. Efficacy and safety ot a new vaginal contraceptive formulation containing high molecular weight poiy(sodium 4-styrencsulfonate). Biology of Reproduction 66, 886-894; US patent 6230182), polymethylene hydroquinone sulfonate (US patent 6239182), dextran sulfate (Baba M, Schols D, Pauwels R, Nakashima H, De Clercq E. 1990. Sulfated polysacchandes as potent inhibitors of HIV-induced syncytium formation: a new strategy towards AIDS chemotherapy. Journal of Acquired Immune Deficiency Syndrome 3, 493-9), sulfated polyvinyl alcohol (Baba M, Schols D, De Clercq E, Pauwels R, Nagy M, Gyorgyi-Edelenyi J, Low M, Gorog S. 1990. Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency vims replication and giant cell formation. Antimicrobial Agents and Chemotherapy 34, 134-138), and sulfated copolymer of acrylic acid with vinyl alcohol (PAYAS) (Baba M, Schols D, De Clercq E, Pauwels R, Nagy M, Gyorgyi-Edelenyi J, Low M, Gorog S. 1990. Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency vims replication and giant cell formation. Antimicrobial Agents and Chemotherapy 34, 134-138), etc. are being developed as microbicides. The problems of rapid spread of sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS) are steadily growing. According to a report, about 340 million cases of curable STDs occurred throughout the world in the year 1999 (http://www.who.int; http://www.flii.org). According to "AIDS epidemic update -December 2001" by UNAIDS (http://www.unaids.org), 40 million people are living with AIDS and about 14000 new HIV infections occurred in a day in year 2001. About 3.97 million people are living with AIDS virus in India, (www.naco.nic.in). Worldwide, women face the greatest risk of acquiring human immunodeficiency virus (HIV) due to substantial mucosal exposure to seminal fluids, high prevalence of non-consensual sex, sex without condom use, and unknown, high-risk behaviors of their partners (NIAID Fact sheet, May 2001, http://www.niaid.nih.gov). Ratio of HIV positive women to men is increasing at a much faster rate. The number of women with HIV infection and AIDS has been increasing steadily worldwide. According to UNAID report, as of December 2001, 17.6 million women were living with HIV/AIDS worldwide, accounting for 47.3 percent of the 37.2 million adults living with HIV/AIDS (hup: www.unaids.or^). Despite taking all the precautions to control its further spread, HIV positive females can't control its transmission to progeny. Looking at these facts, need of preventive measures for women is more as compared to men. Attempts at developing vaccine against HIV have been unsuccessful so far, mainly because of the "dynamic" nature of virus. Drugs, which can cure the infection, although expensive, have shown a reasonable degree of success in extending the life span of those who are already infected. Attempts at limiting the spread of STDs and AIDS, through standard prevention tools such as use of condoms and behavioral modifications (monogamy and sex abstinence) have proven inadequate. Under these conditions, a new category of prophylactic agents and formulations called "microbicides" are being developed with a hope, to control and put a stop to the rapid spread of STDs (Harrison, P.P. 2000 Microbicides: Forging scientific and political alliances. AIDS Patient Care and STDs 14, 199-205). These preparations are targeted for vaginal or rectal use and can be designed with and without contraceptive activity. They can also have a therapeutic benefit on sexually transmitted infections such as those caused by Candida sp., Chltimydia truchomatis, Neisseria gonorrhea, Trichomonas vaginalis etc. Vaginal and/or rectal microbicides can provide an alternative consumer friendly, protective methodology under the control of women to provide such protection. The vagina, in addition to being a genital organ with functions related to conception, serves as potential route for daig administration. Mainly used for local action in the cervico-vaginal region, it has the potential for delivering drugs for systemic effects and uterine targeting. Traditionally vaginal cavity has been used for the delivery of locally acting drugs such as antibacterial, antifungal, antiprotozoal, antiviral, labor-inducing and spermicidal agents, prostaglandins and steroids. Several types of conventional vaginal dosage forms (VDFs) such as tablets, hard and soft gelatin capsules, creams, suppositories, pessaries, foams, ointments, gels, films, tampons, vaginal rings and douches are available. These suffer from various limitations such as leakage, messiness and low residence time, which contribute to poor subject or patient compliance. So there is a strong critical need to develop better dosage forms, which can meet the clinical as well as the user's requirements. Attempts are being made to develop novel vaginal drug delivery systems. Novel developments such as bioadhesive systems and liposomes overcome some of the major limitations of conventional vaginal products. As of now, only gels have been formulated using such compounds. CS and PSS are difficult to formulate in unit solid dosage forms as these are high molecular weight compounds and moreover form a matrix when come in contact with water thus interrupting the further ingress of water into the core resulting in poor dispersion of dosage form and release of medicament. There is a critical need to formulate these compounds into solid unit dosage forms in order to quantify the dose accurately so as to make it more patient compliant. Sexually transmitted diseases (STDs) of bacterial origin that can be cured are the most common cause of illness worldwide. These can lead to long-term complications with serious social, heath and economic consequences. The estimated annual (1995) worldwide incidence of four major curable STDs, namely syphillis, gonorrhea (Neisseria gonorrhoeae), chlamydial infection and trichomoniasis, was about 330 million (Gerbase AC, Rowley JT, Heymann DHL et al. 1998. Global prevalence and incidence estimates of selected curable STDs. Sex. Transmitted Infections, 74, S12-S16). Apart from this AIDS is the major killer from the group of sexually transmitted disease of viral origin. There has thus heretofore been desired the development of preventive or curative agents from inexpensive, widely available resources, with broad antiviral and antibacterial activities. The development of safe and effective microbicides fulfilled the above necessities. Cellulose sulfate and polystyrene sulfonate are the two high molecular weight non-cytotoxic microbicidal compounds of polymeric nature with proven microbicidal activity. As per US patent 6063773 cellulose sulfate at concentration of 0.005% inhibits the binding of HIV to human cells in vitro, at concentration as low as 0.00001%, it inhibits infection of human cells by HSV in vitro, at a concentration of at least 0.01% can completely kill the bacteria N. gonorrhea and moreover it had no adverse effect on the normal vaginal flora (Lactobacillus gasseri). Moreover, the addition of cellulose sulfate in a concentration as low as 0.00001% is effective in inhibiting the infection of human cells by viral pathogens in vitro. The activity of cellulose sulfate is not affected by incorporating it in the present novel pharmaceutical composition as evident by the results of HI assay. Similarly according to US patent 6239182, PSS also inhibits the HIV virus with an IC gonococci with an ICsn of about 3 ug/ml, and chlamydia multiplication at 1 ug/ml. Apart from the inhibiting sexually transmitted pathogens, both the compounds are contraceptive without significant cytotoxic effects. PSS inhibits a number of enzymes, including sperm hynluromdase reversihly vvhereas CS induces acrosomal loss in human spermatozoa and impedes the penetration by spermatozoa into the cervical mucus membrane /// viiro. The compounds have shown to have generally fewer side effects than conventional vaginal contraceptives (e.g., nonoxynol-9). Different types of vehicles are reported for incorporating medicament in capsule dosage form. US patent 4695450 describes the utilization of anhydrous emulsion with an oil phase (o) and a hydrophilic phase (p) of water-soluble but anhydrous liquids, as a filler matrix for medicinal preparations in capsules. The anhydrous liquids were selected from polyethylene glycols of different molecular weights, dihydric alcohols, particularly propylene glycol, or tnhydric alcohols, particularly glycerol or mixtures thereof. But the use of such anhydrous agents results in brittleness of the shell as they have shown to withdraw water from the gelatin shell. The present invention does not contain any ingredient, which has adverse effect on gelatin shell. Moreover the present composition is thixotropic in nature as compared to the invention described above. This prevents the leakage of contents from capsule on storage. According to US patents 4620974; 4777048 and 4832952, the use of liquid, non-solubilizing, hydrophilic lubricants markedly improves the dissolution rates of pharmaceutical composition contained in a hard gelatin capsule. They have used polyethylene glycols (in the molecular weight range of 200 to 900) along with active ingredient. There are number of reports, which states that polyethylene glycols (PEGs) are incompatible with hard gelatin capsule shell. PEGs take up water from the gelatin shell and thus make it brittle. The present invention contains all the ingredients, which are compatible with the gelatin shell and has been shown to be stable on accelerated stability conditions. US patent 4795642 discloses a pharmaceutical composition comprising a gelatin capsule enclosing a solid matrix formed by the cation-assisted gellation of a liquid fill incorporating vegetable gum and a pharmaceutically-active compound. In this embodiment, a dispersion or solution containing active ingredient and a vegetable gum as a bulking agent in capsule and than a gelling agent is added to this liquid filled capsules so as a matrix is formed in situ, which results in controlled release of medicaments after the rupture ol capsule. Such kind of in situ gellation is not preferable, as one cannot assess the changes happening inside the shell after addition of the gelling agent. Moreover this may result in large variability in release pattern with each dose as gelling takes place inside the sealed capsule. The properties of capsule shell may also be adversely affected by in situ gellation. The present invention does not involve such a complex and cumbersome procedure for preparing liquid/semisolid filled capsules and is very simple in design. Liquid capsule formulations for vaginal use have been reported for incorporation of lactic acid bacteria dispersed in pharmaceutically acceptable carrier with viscosity range of 2000-4000 cPs. The vehicle selected contained oil and corn starch in order to preserve the integrity of the bacterial culture and to stabilize the formulation. Similarly, US patent 6365180 relates to the use of liquid or semi-solid compositions for filling into capsules for oral use. The invention dictates the use of active agents with at least one terminal ester group or chemically active moiety, which is removed or hydrolyzed in-situ. This patent makes an attempt to decrease the irritation potential of non-steroidal anti-inflammatory agents on incorporating it in liquid or semi-solid composition. Oral liquid composition stated in the above-mentioned patent involves pH modulation to avoid irritation whereas the present invention does not contain any ingredient, which has any reported irritation potential at the concentrations used in formulation for vaginal use. The present invention does not restrict itself to the use of moieties containing chemically active groups. Also, the present invention does not contain any solubilising agent or plasticizer. Oil based drug delivery systems for hydrophobic drugs are described in US patent 5645856. US patent 6365181 reports the use of a thixotropic gelatin vehicle for filling into hard or soft gelatin capsules. The composition comprises of vegetable oil, viscosity modifier and surfactant. US patent 5738871 describes the use of hard gelatin capsules for delivery of fat soluble ingredients. The present invention not only incorporates some of the features of the above reported patents but also is especially suitable for incorporating high molecular weight compounds in specific. Moreover the present formulation is bioadhesive in nature and has excellent retention properties. US patent 6165493 relates to administration of cellulose acetate phthalate (CAP) or hydroxypropyl methylcellulose phthalate (HPMCP), such as in micronized form, or a combination thereof, either alone or in combination with a pharmaceulically acceptable carrier or diluent for reducing the transmission of AIDS. According to inventors, the particularly preferred composition for these compounds is a micronized preparation containing CAP or micronized HPiMCP, a Poloxamer and distilled acetylated monoglycerides (a mixture of micronized CAP, poloxamer and acetylated monoglycerides is sold by the FMC Corporation under the trade name "AQUATERIC") suspended in glycerol. This formulation according to inventors can be dispensed in capsule dosage form. The present invention describes compositions containing high molecular weight compounds. The formulation in present invention does not contain glycerol, which may have an adverse effect on gelatin shell. In addition, the composition in present invention is bioadhesive in nature. It is more specifically designed to deliver these compounds topically in capsule dosage form in order to reduce costs and avoid possible disposal problems. The incorporation of high molecular weight compound in hard gelatin capsule is itself a challenge, which the present invention fulfills. It involves simple and efficient manufacturing process. Moreover the present invention discloses a formulation that possesses fast dispersion properties and is bioadhesive in nature in order to provide an intimate contact with vagina. US patents 5514670, 5744155 and 5993846 relate to preparation of bioadhesive lipid-in-water emulsion for administering peptides along with absorption promoters. The high molecular weight peptides were incorporated into the inner lipid phase and lyophilized, which may be incorporated into capsules. On coming in contact with aqueous phase, it forms a continuous emulsion. The present invention is designed for incorporating high molecular weight compounds into capsules. At the same time, it does not involve any sophisticated and costly processes like lyophilization. The carrier phase of the present invention is thixotropic, bioadhesive and water swellable and is best suited for formulating high molecular weight compounds. CS (US patent 6063773) and PSS (US patent 6239182) are non-cytotoxic contraceptive antimicrobial agents, currently under clinical stages of development. Phase 1 clinical studies for both CS gel (6% w/w) and PSS gel (10% w/w) have been successfully completed. Both the compounds exhibit antimicrobial activity against sexually transmitted pathogens including HIV. Based on the in-vitro and animal experiments CS and PSS have proven to be effective and safe for use in reducing the risk of infection associated with STD causing pathogens and for contraception. The gels used in these prior arts are aqueous based gels. The present invention relates to vaginal capsules containing sodium cellulose sulfate (CS) or sodium polystyrene sulfonate (PSS) as active material, along with different excipient, which are non-aqueous in nature. OBJECTS OF THE INVENTION The main object of the invention was to formulate high molecular weight compounds in such a dosage form that is hydrophobic in nature, so that these do not swell during production, storage, handling, and administration. But as soon as the formulation is administered into vagina or rectum and comes in contact with vaginal secretions it should swell and form a smooth, homogenous, viscous and bioadhesive gel. At the same time, formulation should rapidly disperse, disintegrate and release the active moiety within few minutes of administration Another object of the present invention is to provide a novel pharmaceutical composition useful for incorporating high molecular weight compounds, which obviates the drawbacks and possess desired characteristics as detailed above. Another object of the present invention is to provide a elegant dosage form incorporating high molecular weight microbicidal agent for reducing the frequency of transmission and prevention of STDs and AIDS. The other object of the present invention is to formulate high molecular weight compounds in a thixotropic medium that is liquid at high temperature and hence can be easily filled into capsules. On the other hand, it solidifies at room temperature, thus avoids the leakage during handling and storage. Another object of the present invention is to provide a pharmaceutical composition that is hydrophobic in nature during formulation but should be totally water swellable when comes in contact with water.Another object of the present formulation is to provide a novel pharmaceutical composition, which is bioadhesive in nature and retains well in vagina. Also the object of the present formulation is to provide a useful pharmaceutical composition, which is simple in design, involves less number of manufacturing steps and is easily amenable to mass production. Yet another object of the present invention is to provide a composition that can be useful for filling both in hard gelatin, soft gelatin and non-gelatin capsules. Yet another object of the present invention is to provide a safe and relatively inexpensive method for vaginal and rectal delivery of drugs and pharmaceuticals. Other objects, features, and advantages of the formulation will be more apparent to those versed in the dispensing art from reading the detailed description of the specification, taken in conjunction with the drawing figures and accompanying claims. s i \ rr.vir.N r or 11 ir. INVENTION A pharmaceutical composition for vaginal and rcclal administration to prevent sexua1ly transmitted disease (STDs) and acquire immunodeficiency syndrome (AIDS). Inning rapid dispersability in water to form a smooth, homogeneous, viscous and bioadhesive gel. the said composition comprising of a high molecular weight active ingredient in the range of 0.5 lo50 % w/w, hydrophobic vehicle in the range of 20 to 90% w/w. dispersing agent in the range of 0.1 to 10% w/w. a water swellable bioadhesive agent in the range of 0.5 to 45% w/w. and optionally a viscosity modifying agent in the range of 0.5 to 45.0% such as herein described. SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition for vaginal or rectal administration to prevent sexually transmitted diseases (STDs) and Acquired Immunodeficiency Syndrome (AIDS). BRIEF DESCRIPTION OF DRAWINGS AND TABLES Figure 1. Thixotropic behavior of the CS capsule fill material measured using programmable Brookfield RVDV III + Programmable Rheometer (Brookfield Engineering, USA) and Rheocalc 2.1 software. Figure 2. Thixotropic behavior of the PSS capsule fill material measured using programmable Brookfield RVDV III + Programmable Rheometer (Brookfield Engineering, USA) and Rheocalc 2.1 software. Table 1. Physico-chemical characteristics of fill material for CS and PSS capsules Table 2. Physico-chemical characteristics of CS and PSS capsules Table 3. Bioadhesive strength and work of adhesion (average of 5 replicates ± standard deviation) of capsules as compared to other vaginal formulations currently underdevelopment or in market. Table 4. Retention properties of capsules as compared to other vaginal formulations currently underdevelopment or in market. DETAILED DESCRIPTION OF PRESENT INVENTION Accordingly, the present invention provides a high molecular weight polymeric compounds (polystyrene sulfonate and cellulose sulfate) with proven microbicide activity are dispersed in an oil base containing a dispersing agent, bioadhesive agent and a viscosity enhancing/solidifying agent. The present invention discloses the composition and method for manufacturing of a thixotropic, water swellable, and bioadhesive formulation of high molecular weight active(s) for filling into capsule forms for vaginal or rectal administration. The composition is simple, easy to prepare, and involves very few steps for preparation. The capsules prepared show very fast and uniform dispersion in water and result in formation of a viscous bioadhesive gel, which is totally water-soluble. The capsule fill material and formulation was found to be fairly stable and consistent in performance after accelerated stability study. An embodiment of the present invention provides a synergistic pharmaceutical composition for vaginal or rectal administration to prevent sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS), also having rapid dispersibility in water to form a smooth, homogeneous, viscous and bioadhesive gel, the said composition comprising: w/w (%) i) a high molecular weight active ingredient 0.5 to 50.0% ii) a hydrophobic vehicle 20 to 90.0% iii) a dispersing agent 0.1 to 10.0% iv) a water swellable bioadhesive agent 0.5 to 45.0% v) optionally, a viscosity modifying agent 0.5 to 45.0% An embodiment of the present invention wherein a preferable synergistic composition comprises of: w/w (%) i) a high molecular weight active ingredient 8.0 to 30.0% 11) a hydrophobic vehicle 40.0 to 80.0% in) a dispersing agent 2.0 to 8.0% iv) a water swellable bioadhesive agent 10.0 to 35.0% v) optionally, a viscosity modifying agent 10.0 to 35.0% An embodiment of the present invention provides a composition having high molecular weight active ingredient which is microbicidal polyanionic polymer selected from phosphorylated hesperidins, sulfonated hesperidins, quercetin sulfate, polyvinyl alcohol sulfate, sulfated copolymer of acrylic acid with vinyl alcohol (PAVAS) polystyrene sulfonates, substituted benzene sulphonic acid formaldehyde co-polymers, sulphuric acid modified mandelic acids, cellulose aceate phthalate, sulfated cyclodextrins, dextrin sulfate, carrageenan, naphthalene sulfonate, polymethylene hydroquinone sulfonic acid, cellulose sulfate, dendrimers, neem oil fractions or derivatives, polystyrene hydantoin elastomer, povidone iodine, Lactobacillus spores and/or mixtures thereof. An yet another embodiment of the present invention provides a high molecular weight active ingredient having molecular weight ranging from 5000 to 3 million Dalton, and above. In still another embodiment provides a composition wherein an oily hydrophobic vehicle is selected from a group consisting of arachis oil, castor oil, cottonseed oil, maize (corn oil), olive oil, sesame oil, soyabean oil, sunflower oil, light liquid paraffin, safflower oil. theobroma oil, coconut oil, silicone oil, paraffin oil, hydrogenated vegetable oil, fish oil, primrose oil, mineral oil, vaseline oil, vegetable oils, animal oils, carbowaxes, glycol esters, i^lycerol esters, macrogol esters, cetosteryl alcohol, cetyl alcohol, lanolin, lanolin alcohols, sorbitan esters, fatty alcohols, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and/or mixtures thereof Still yet another embodiment of present invention provides a composition, wherein the high molecular weight active ingredient used may be hydrophobia or hydrophilic in nature. Still another embodiment of the present invention provides a composition, wherein the dispersing agent is selected from colloidal silicon-di-oxide, white soft paraffin, macrogol glycerides. poloxyethylene castor oil derivatives, mono, di and tri-glyceridcs (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and/or mixtures thereof. Still yet another embodiment of the present invention, provides a composition wherein the bioadhesive agent is selected from a group consisting of acrylic acid polymers, gelatin, tragacanth, sodium carboxymethylcellulose, guar gum, propylene glycol alginate, bentonite, natural gums such as tragacanth, acacia, guargum, xanthan gum etc, alginates, chitosan, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, starches, pectins or mixtures thereof. Still yet another embodiment of the present invention provides a composition, wherein the viscosity modifying agent having thixotropic behaviour is selected from hydrogenated vegetable oil, colloidal silicon-di-oxide, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monostearate, gelatin, natural gums such as acacia, tragacanth, guar gum, xanthan gum or mixtures thereof. Still yet another embodiment of the present invention, the bioadhesive agent used can also act as a viscosity-modifying agent. Still another embodiment of the present invention, the composition used can be incorporated into hard or soft gelatin or non-gelatin capsules. Yet another embodiment of the present invention, the composition viscosity modifying agent with thixotropic property, remains liquid at normal filing temperature about WC and solidifies as the temperature drops down to ambient temperature of about 25°C is used. Still yet another embodiment of the present invention, the composition undergoes fast dispersion, disintegration and the capsule fill material takes about nearly 2 min. to completely disperse after capsule shell disintegration. Still another embodiment of the present invention, the composition having thixotropic till material forms a uniform smooth, homogenous, viscous and sticky gel by coming in contact with water. Yet still another embodiment of the present invention, the composition possessing hioadhesive nature is retained well in vaginal cavity. Yet still another embodiment of the present invention, the composition is obtained by simple manufacturing process involving mixing of ingredients with constant stirring in specific ratio at constant temperature. Yet another embodiment of the present invention the composition involves minimum number of manufacturing steps. Still another embodiment of the present invention the composition used is easily amenable to mass scale production. Still another embodiment of the present invention the composition used is stable under extreme temperature and humid conditions. Yet, still another embodiment of the present invention wherein the pharmaceutical composition retains a biological activity of the ingredients. Yet still another embodiment of the present invention, consisting of a process for the preparation of synergistic pharmaceutical composition, the said process comprising steps of: a) mixing a high molecular weight active ingredient, hydrophobic vehicle, dispersing agent, water soluble bioadhesive agent, optionally with a viscocity modifying agent, b) heating with stirring the mixture of step (a) up to 40 ° C to obtain a dispersion, and c) filling the dispersion of step (b) into gelatin capsules An embodiment of the present invention, pharmaceutical composition consists of a capsule incorporating high molecular weight compounds in an oily liquid base, a dispersing agent, a solidifying agent (hydrogenated vegetable oil), and a bioadhesive agent (a natural gum). Another embodiment of the present invention the retention behavior of capsule dispersion in simulated vaginal environment was studied using isolated sheep vaginal tissue after dispersing the one unit dose in 3 ml of saline. The results of the retention study depict that formulation retains well in vagina. The biological activity of the compounds in present invention is not affected even after 90 days of storage in accelerated stability conditions (40°C and 75% RH) as evident by results of hyaluronidase inhibition (HI) assay. The cellulose sulphate as a compound is 97.16 percent active against hylauronidase at Img/ml concentration. This activity of cellulose sulphate in formulation is not altered even after storage at accelerated storage conditions (40°C and 75% RH) for a period of 90 days. Cellulose sulphate in formulation was found to be 104.62% active against hyaluronidase at 1.25 mg/ml, similar results were obtained for polystyrene sulfonate. The HI activities of 1 ing/ml solution of neat PSS and PSS capsule formulation after 90 days of accelerated stability studies were found to be 77.3 and 60.69% respectively. These compounds neither upset the normal vaginal nor significantly disrupt the protective glycoprotein vaginal coating. As these are high molecular weight compounds, CS and PSS are not absorbed into systemic circulation. But because of their high molecular weight, these are usually difficult to formulate into any elegant solid unit dosage form. An embodiment of the present invention, the present novel pharmaceutical composition formulates the said high molecular weight active in a hydrophobic media such that the formulation during storage or handling does not provide an appropriate media for high molecular weight compound to swell but as soon as this active comes in contact of water, the formulation starts swelling rapidly and forms a gel which when administered uniformly spread in vaginal cavity. The gel formed is bioadhesive in nature and retains well in vagina. The formulation is encapsulated in gelatin or non-gelatin shell. The use of hard gelatin capsule in vagina is slowly gaining impetus. The present invention contains the ingredients that are soluble, chemically and biologically compatible with active ingredients and are either GRAS listed and/or official in pharmacopoeias. The formulation is easily amenable to mass scale production and is flexible in terms of dose range. An embodiment of the present invention, the present formulation is intended for administration into vaginal cavity. The formulation characteristics makes it best suitable for administration into vagina as it gels on dispersion after coming in contact with vaginal secretions as seen in in vitro experiments and thus forming a uniform layer all over, is sufficiently bioadhesive thus increasing the retention in the vaginal cavity, contains all the water soluble or miscible ingredients thus ensuring wash out of remnants out of vaginal cavitv, etc. Yet another embodiment of the present invention, there are varieties of pharmaceutical compositions that use oil or hydrophobic materials to disperse the active ingredient. The liquid or seinisolid hydrophobic vehicles used in the present invention is selected Irom a group consisting of arachis oil, castor oil, cottonseed oil, maize (corn oil), olive oil, sesame oil, soyabean oil, sunflower oil, light liquid paraffin, safflower oil, theobroma oil, coconut oil, silicone oil, paraffin oil, hydrogenated vegetable oil, fish oil, primrose oil, mineral oil, vaseline oil, vegetable oils, animal oils, carbowaxes, glycol esters, glycerol esters, macrogol esters, cetosteryl alcohol, cetyl alcohol, lanolin, lanolin alcohols, sorbitan esters, fatty alcohols, mono, di and tri-glycerides (modified or unmodified) based on edible tats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstosteanc acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and mixtures thereof. Still yet another embodiment of the present invention the materials that can be used as dispersing agents are selected from a group of colloidal silicon-di-oxide, white soft paraffin, macrogol glycerides, poloxyethylene castor oil derivatives, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and mixtures thereof. Still another embodiment of the present invention, materials that can be used as bioadhesive or gel forming agents are selected from a group consisting of acrylic acid polymers, gelatin, tragacanth, sodium carboxymethylcellulose, guar gum, propylene glycol algmate, bentonite, natural gums such as tragacanth, acacia, guargum, xanthan gurn etc, algmates, chitosan, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, starches, pectins or mixtures thereof. An embodiment of the present invention provides the use of viscosity modifying agent having thixotropic behaviour is selected from hydrogenated vegetable oil, Aerosil (colloidal silicon-di-oxide), diethylene glycol monostearate (Hydrine), ethylene glycol monostearate (Monthvie), glyceryl monostearate (Pearlescent agent), gelatin, natural gums such as acacia, tragacanth, guar gum, xanthan gum or mixtures thereof. In light of the above discussion, it will be readily appreciated by those versed in the subject art that a critical need exists for a novel pharmaceutical composition useful in delivering high molecular weight compounds, which is simple in design, involves less number of manufacturing steps, disperses rapidly and uniformly when administered, bioadhesive in nature and is easily amenable to mass production. Capsules are the most flexible and versatile of all dosage forms. These require minimal excipients to formulate any compound. Capsules provide a means to accurately deliver the measured dose for rectal and vaginal application. Capsule also provides a protective shell for moisture sensitive compounds The pharmaceutical composition is simple in design and is easy to manufacture. It involves only mixing and filling the dispersion in capsules. The present novel pharmaceutical composition represents a state-of-art to formulate capsules containing high molecular weight compounds that form a smooth, homogenous, viscous, and bioadhesive gel after dispersion in fluid. During formulation development and production these compounds are difficult to handle as these form gel and block the nozzle of the delivering devices or pumps. Even when these are formulated as solid dosage forms, a gel layer is formed in contact with water, which prevents the further entry of water into solid core and thereby slowing down the further penetration of fluid and disintegration of the solid dosage form. For the compound to be delivered through vaginal route it should provide complete and fast dispersion of the actives ingredients. Incorporating high molecular weight compounds into rapidly dispersible formulations is again a challenge. The present invention overcomes this challenge. The above composition is not a mere admixture. In fact, it is a synergistic composition having unexpected properties which are not anticipated or obvious to a person skilled in the art. The properties such as smoothness, longitivity, viscosity and bioadhesion arc excellent when compared with conventional compositions. EXAMPLES The following examples are given by the way of illustration and therefore should not he construed to limit the scope of the present invention. Example 1: One example of the present invention is the capsule containing PSS (PSS capsules) as high molecular weight agent. The composition is as follows: (Table Removed) Soyabean oil was weighed and to it added mixture of Labrafil and melted hydrogenated oil with continuous stirring at 40°C. To the above mixture xanthan gum was added followed by sodium polystyrene sulfonate. The uniform dispersion was than filled in hard gelatin capsule (size 00). Temperature was maintained to 40°C during preparation of fill material and filling into capsule shells. Physico-chemical characteristics of the fill material and capsules are mentioned in Table 1 and Table 2 respectively. Example 2: Another example of the present invention is the capsule containing CS (CS capsules) as high molecular weight agent. The composition is as follows: (Table Removed) Sodium cellulose sulfate was mixed with soyabean oil for 10-15 min with continuous stirring. Xanthan gum was then added to the above dispersion followed by mixture of dispersing agent and solidifying agent The uniform dispersion was filled in hard gelatin capsules. Temperature was maintained to 40°C during processing. Physico-chemical characteristics of the fill material and capsules are mentioned in Table 1 and Table 2 respectively. Example 3: Process for the preparation of pharmaceutical composition The pharmaceutical composition, in present invention, is manufactured by simple mixing the ingredients in a specific order while maintaining a constant temperature of 40°C. The actual process in case of sodium polystyrene sulfonate involves mixing of oil or hydrophobic vehicle with the said dispersing agent and melted hydrogenated vegetable oil. To the above mixture bioadhesive agent is added followed by the addition of above said active with constant stirring at 40°C. The uniformly formed dispersion is than filled in 00 size capsules. Liquid filling into hard gelatin capsule results in reducing the cross-contamination due to dust generation and has shown to reduce weight variation to about 1% as compared to powder filling in hard gelatin capsule. The liquid filling results in development of efficient and cost effective process. Apart from this, if the formulation is thixotropic in nature, as in present case, the material solidifies after filling and thus reduces the possibility of leakage from capsule shells. In case of sodium cellulose sulfate the manufacturing process involves the pre-mixing of cellulose sulfate in oil. Bioadhesive agent from the above said group is added to the above dispersion. To the thick mass, formed mixture of dispersing agent and thickening agent is added slowly with constant stirring. The temperature above 40°C and a constant rate of stirring should be maintained throughout the stirring. Example 4: EVALUATION OF PERFORMANCE CHARACTERISTICS The performance of present pharmaceutical invention was evaluated by conducting following tests: Visual examination The formulated capsule fill material and capsules were visually examined for following parameters: • Colour and Odor: These are characteristic subjective parameters for a given formulation. Change in colour of the composition during storage is depictive of some chemical change, if any. • Consistency; Ideally capsule fill material should be liquid while filling and should solidify after filling in order to reduce the leakage. When samples were removed from stability chambers (4()°C and 75% RH), the consistency (i.e., liquid, semi-solid, solid) of the formulation was recorded. • Separation: Formulation was left undisturbed and was observed for separation of layers if any at different time intervals. • Lumps: The capsule fill material should ideally be free of any lumps as they block the nozzle of the delivering device or pumps resulting in non-uniform filling. The formulation was observed for any lump formation during batch preparation. • Nature of formulation before and after dispersion in water was observed and recorded. • Nature of gel formed after dispersion: The gel formed was observed for smoothness or roughness, thick or thin, fibrous or non-fibrous nature, uniform or non-uniform, stickiness etc. • Any other physical change was also observed. Settling The capsule fill material and capsules were left undisturbed. If any settling is visible, that was reported as distinct or clear or no settling observed. Kate of settling If any settling is observed then the sample was heated so that it liquefies, kept undisturbed for half-an-hour and examined thoroughly. The rate of settling is ranked as very fast (settling within 5 min), fast (settling within 5-10 min), and slow (settling in more than 1 5 min). Redispersibility If case of settling of dispersion, the glass vial containing dispersion was shaken vigorously and redispersibility was recorded and ranked as fast (if redisperses within 5 min), slow (redisperses on shaking for 10 -15 min), and not redispersible (if no redispersion occurs after 15 min of vigorous shaking). Dispersion Behavior Measured about Igm of dispersion accurately and poured it in a glass beaker containing 10 ml of demineralised water at 37°C in a beaker placed on a magnetic stirrer with thermostatic control. The dispersion was stirred at a constant rpm. Following parameters were recorded as follows: Time o f start of dispersion (min) Time of completion of dispersion (min) Dispersion behavior (uniform, not uniform, pattern of dispersion, any other factor) Disintegration test Disintegration time and behavior of capsules were evaluated with an in house developed in vitro method (Garg S, Vermani K, Gunjan, Waller DP, and Zaneveld LJD. 2002 Survey of vaginal formulations available in Indian market; physico-chemical characterization of selected products. International Journal of Pharmaceutical Medicine, in press). A defined volume of disintegrating fluid (10 ml) was taken in a cylindrical container fitted with a screen (BSS mesh # 10), maintained at 37°C and stirred at fixed rpm (300) with the help of magnetic stirrer. Test capsules were placed above the screen and disintegration time recorded. A capsule was considered to disintegrate when all the contents came out of the partially dissolved capsule shell. Disintegration was studied using water as disintegrating fluid. Disintegration time and behavior were recorded. Different parameters recorded are: ••• Time at which capsule starts disintegrating (min) J Time of completion of disintegration (min) •I* Different visual observations during disintegration pH measurement of the formulation after dispersion The pH of dispersion was measured at ambient temperature using a calibrated pH meter (Denver 220 pH conductivity meter, USA) fitted with a glass electrode. The pH meter was calibrated using certified buffers of pH 4, 7, and 10 (Fisher Scientific, USA). Viscosity The basic purpose of determining the viscosity of formulation after dispersion was to assess the in vivo behaviour of the formulation after capsule disintegration. Change in different rheological parameters during stability studies also help in predicting the changes occurring in formulation. Viscosities of the fill dispersion (1 gm) diluted with water (20 ml) were measured using a Brookfield RVDV III+ Programmable Rheometer (Brookfield Engineering, USA) with coaxial cylinders (measuring spindle - SC4 21). For viscosity measurement, spindle was rotated at 20 rpm in case of example 1 (PSS capsules) and at 50 rpm in case of example 2 (CS capsules) for 1 minute. Viscosity measurements were done at 25°C. Viscosities of the dispersions of CS and PSS capsules in 20 ml of water (30°C) were compared to that of a marketed vaginal capsule formulation (Puregest, vaginal soft gelatin capsules containing progesterone, marketed by Sun Pharmaceutical Industries Ltd.). Viscosity was measured using Brookfield RVDV 111+ Programmable Rheometer with cylindrical spindle (SC4 21), rotated at 50 rpm for 1 minute. Rheology The aim of the present study was to assess the type of flow and thi.xotropic or antithixotropic nature of the formulation. Thixotropic property was studied by applying an increasing amount of shear to the formulation at a constant interval and than decreasing the shear at a constant interval in the same manner. Various parameters were recorded and graphs are plotted between shear stress Vs shear rate and viscosity Vs shear rate to assess the flow behaviour of the formulation. An ideal formulation should be uniform, non-lumpy and thi.xotropic for manufacturing (to allow filling into capsule shells) as well as storage to avoid leakage. Viscosity was measured as a function of speed using a Brookfield RVDV III+ Programmable Rheometer with coaxial cylinders (measuring spindle - SC4-14), connected to a Pentium PC with Rheocalc Version 2.1 software. For rheological evaluation, shear rates (y) in the range of 48 to 96 s"1 were chosen and each one of them maintained for 30 sec at 25°C. Measurements were made of viscosity (r\|) and shear stress (a) on increasing the shear rate (up curve) until the maximum rate was reached. Measurements of r\| and a were then repeated by decreasing shear rate until the minimum value, providing the down curve. Bioadhesion The method to measure bioadhesion is based on the principle of measuring the force required to break the adhesive bond between a model membrane and test formulation. Isolated sheep vaginal mucosa was used as the model membrane (Institute animal ethics committee's permission was obtained for the use of isolated sheep vagina in the experiments). The test formulation is sandwiched between two model membranes fixed on flexible supports in the modified probes of texture analyzer for a sufficient period of time. After the adhesive bond has formed, the force required to separate the bond is measured as bioadhesive strength. Bioadhesive strength of vaginal formulations was measured using a calibrated texture analyzer (Model TA-XT21, Stable Micro Systems, UK) equipped with a 5 kg load cell and modified probes. Data was acquired at a rate of 50 points per second, using fully integrated data acquisition and analysis software, i.e. Texture Expert Version 1.22. A previously reported method (Vermani K, Garg S, Zaneveld, LJD. 2002, Assemblies for //; vitro measurement of bioadhesive strength and retention characteristics in simulated vaginal environment. Drug Development and Industrial Pharmacy, 28 (9), 1129-1142) was modified to measure bioadhesion using Texture analyzer. The probes of equipment were modified so as to hold and provide a flexible support to sheep vaginal mucosa. Sheep (Ovis aries, non descriptive local breed) vaginal tissue was obtained immediately after the sacrifice of animals at a slaughterhouse. Vaginal tissue was cleaned, separated from the supporting muscular and connective tissues taking care to maintain the integrity of mucosa. The isolated tissue was frozen at -20°C till further use. Before experiments, sheep vaginal tissue was thawed in normal saline containing 0.1% w/v Sodium azide as preservative. After thawing, vaginal tube was incised longitudinally and tied to the modified probes with mucosal side exposed, using a thread. For measuring bioadhesive strength, 0.5 gm of the dispersion (single unit dose of capsule dispersed in 3 ml normal saline), was applied in between the sheep vaginal mucosa on an area of 464 mm2. Membranes were kept in contact with the test sample for a period of 5 minutes under a constant force of 0.25 N in order to establish a proper contact between membrane and sample to allow the formation of adhesive bond. Force required to separate the two membranes (with dispersion in between) was measured by upper support of texture analyzer moving at a rate of 0.1 mm/sec. Maximum force required to break the adhesive bond was measured as bioadhesive strength and area under curve was measured as work of adhesion. All the formulations were evaluated using isolated sheep vaginal mucosa (n = 5) and mean bioadhesive strength and work of adhesion were determined. Retention The assembly to measure retention of a formulation in vaginal cavity is based on the principle of measuring the weight of formulation falling down under the influence of gravity, from an intact tubular portion of sheep vagina, suspended in vertical position and maintained at 27±1°C and 75±2% RH (Vermani K, Garg S, Zaneveld, LJD. 2002, Assemblies for in vitro measurement of bioadhesive strength and retention characteristics in L^J vaginal environment, Drug Development and Industrial Pharmacy, 28 (9), 1129-1142). Dispersion of vaginal formulation, placed inside a vertically suspended excised sheep vaginal tube, was allowed to fall under the influence of gravity. The weight of formulation fell down, as a function of time, was recorded. The experiment was repeated with isolated sheep vaginal tissue placed at angle of 45 degrees to the horizontal. Bioadhesive and retention properties of CS and PSS capsules were compared to that of Replens gel, (Columbia Laboratories, Aventura, FL, claimed to have bioadhesive properties), KY Jelly" (Advanced Care Products, Raritan, NJ; a frequently used marketed vaginal lubricant), Acidform gel (an investigational acid buffering bioadhesive vaginal gel formulation being developed at TOPCAD, Rush Presbyterian St Luke's Medical Center, Chicago, LfSA, presently in clinical trials), CS gel (6% w/w gel, presently in clinical trails) and PSS gel (10% w/w gel of PSS, presently in clinical trials). Example 5: Hyaluronidase inhibition assay The activity of the present actives against hyaluronidase is well established. The aim of present investigation is to see that whether the incorporation of said actives in the formulation affects its activity against hyaluronidase or not. Activity against hyaluronidase is quantified by measuring the extent of hyaluronic acid hydrolysis. This is measured by determining the concentration of N-acetylglucosamine-reactive material, resulting from enzyme action using a specrophotmetric method. If the amount formed in the reaction is less than control in the presence of a test material, this indicates a potential inhibition of the enzyme hyaluronidase, which performs the acid hydrolysis. The method of assay is based on the principle originally described by Aronson and Davidson (Lysosomal hyaluronidase from rat liver. I. Preparation, Journal of Biological Chemistry 242 (3), 437-440). The colorimetric determination of N-acetylglucosamine at 545nm (Reissig JL, Strominger JL, Leloir LF. 1955. A modified colorimetric method fo rthe estimation of N-acetylamino sugars. Journal of Biological Chemistry, 217, 959-966) is used to quantify hyaluronic acid hydrolysis by bovine testicular hyaluronidase. The method has been modified such that the acetate buffer used in the hyaluronidase reaction mixture is neutralized with NaOH before the borate buffer is added. The spectral absorbance at 545 nm is read, and compared to absorbance readings obtained with N-acetylglucosamine standards that have been reacted with p-dimethylaminobenzaldehyde. Main advantages of the Invention: a) The present invention provides easy and economical process for the preparation of the present pharmaceutical composition. b) The pharmaceutical composition of the present invention is amenable for filling into hard and soft gelatin and as well as non-gelatin capsules. c) The pharmaceutical composition of the present invention has fewer side effects than conventional vaginal contraceptives. d) fhe pharmaceutical composition of the present invention neither upset the normal vaginal nor significantly disrupts protective glyco protein vaginal coating. e) Active high molecular ingredients of the present pharmaceutical composition are not absorbed into systemic circulation. REFERENCES: 1. Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Andrology 23, 426-438 2. Baba M, Schols D, Pauwels R, Nakashima H, De Clercq E. 1990. Sulfated polysaccharides as potent inhibitors of HIV-induced syncytium formation: a new strategy towards AIDS chemotherapy. Journal of Acquired Immune Deficiency Syndrome 3, 493-499 3. Baba M, Schols D, De Clercq E, Pauwels R, Nagy M, Gyorgyi-Edelenyi J, Low M, Gorog S. 1990. Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency virus replication and giant cell formation. Antimicrobial Agents and Chemotherapy 34, 134-138 4. Garg S, Vermani K, Gunjan, Waller DP, and Zaneveld LJD. 2002 Survey of vaginal formulations available in Indian market; physico-chemical characterization of selected products. International Journal of Pharmaceutical Medicine, in press. 5. Gerbase AC, Rowley JT, Heymann DHL et al. 1998. Global prevalence and incidence estimates of selected curable STDs. Sex. Transmitted Infections, 74, S12-S16 6 Harrison, P.P. 2000 Microbicides: Forging scientific and political alliances. AIDS Patient Care and STDs 14, 199-205 7 Zaneveld LID, Waller DP, Anderson RA, Chany C, Rencher WF, Feathergill K, Diao XH, Donccl GF, Herold B, Cooper M. 2002. Efficacy and safety of a new vaginal contraceptive formulation containing high molecular weight poly( sodium 4- styrenesulfonate). Biology of Reproduction 66, 886-894 US Patent Documents (Table Removed) Tabel 1. Physico-chemical characteristics of fill material for CS and PSS capsules (Table Removed) Table 2. Physico-chemical characteristics of CS and PSS capsules (Table Removed) Table 3. Bioadhesive strength and work of adhesion (average of 5 replicates + standard deviation) of capsules as compared to other vaginal formulations currently underdevelopment or in market. (Table Removed) Table 4. Retention properties of capsules as compared to other vaginal formulations currently underdevelopment or in market. (Table Removed) Retention was measured by suspending the isolated sheep vaginal tissue vertically Retention was measured by placing the isolated sheep vaginal tissue inclined at an angle of 45 decrees to the horizontal We Claim: 1. A pharmaceutical composition for vaginal and rectal administration to prevent sexually transmitted disease (STDs) and acquire immunodeficiency syndrome (AIDS), having rapid dispersability in water to form a smooth, homogeneous, viscous and bioadhesive gel, the said composition comprising of a high molecular weight active ingredient in the range of 0.5 to 50% w/w, hydrophobic vehicle in the range of 20 to 90% w/w, dispersing agent in the range of 0.1 to 10% w/w, a water swellable bioadhesive agent in the range of 0.5 to 45% w/w, and optionally a viscosity modifying agent in the range of 0.5 to 45% such as herein described. 2. A pharmaceutical composition as claimed in claim 1, wherein the said composition preferably comprises a high molecular weight active ingredient in the range of 8 to 30% w/w, hydrophobic vehicle in the range of 40 to 80%> w/w, dispersing agent in the range of 2 to 8% w/w, a water swellable bioadhesive agent in the range of 10 to 35% w/w, and optionally a viscosity modifying agent in the range of 10 to 35%. 3. A pharmaceutical composition as claimed in claim 1, wherein the high molecular weight active ingredient is a microbicidal polyanionic polymer selected from a group consisting of phosphorylated hesperidins, sufonated hesperidins, quercetin sulfates, polyvinyl alcohol sulfate, sulfated copolymer of acrylic acid with vinyl alcohol (PAVAS), polysterene sulfonates, , substituted benzene sulphonic acid formaldehyde copolymers, sulphuric acid modified mandilic acid, cellulose acetate phthalate, sulfated cyclodextrin, dextrin sulfate, carrageenan, naphthalene sulfonate, polymethylene hydroquinone sulfonic acid, cellulose sulfate, dendrimers, neem oil fractions its or derivatrives, polystyrene hydantoin elastomer, povidine iodine, lactobassilus sporesand/or mixture thereof. 4. A pharmaceutical composition as claimed in claim 1, wherein an hydrophobic vehicle is selected from a group consisting of arachis oil, castor oil, cottonseed oil, maize (corn oil), olive oil, sesame oil, soyabean oil, sunflower oil, light liquid paraffin, safflower oil, theobroma oil, coconut oil, silicone oil, paraffin oil, hydrogenated vegetable oil, fish oil, primrose oil, mineral oil, Vaseline oils, animal oils, carbowaxes, glycol esters, glycerol esters, macrogol esters, cetosteryl alcohol, cetyl alcohol, lanolin, lanolin alcohols, sorbitan esters, fatty alcohols, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and/ or mixtures thereof. 5. A pharmaceutical composition as claimed in claim 1, wherein the dispensing agent is selected from colloidal silicon-di-oxide, white soft paraffin, macrogol glycerides, poloxyethylene castor oil derivatives, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acidsd, and/or mixtures thereof. 6. A pharmaceutical composition as claimed in claim 1, wherein the bioadhesive agent is selected from a group consisting of acrylic acid polymers, gelatin, tragacanth, sodium carboxymethylcellulosc, guar gum, propylene glycol alginate, bentonite, natural gums such as tragacanth, acacia, guargum, xanthan gum, alginates, chitosan, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, starches, pectins and/or mixtures thereof. 7. A pharmaceutical composition as claimed in claim 1, wherein the viscosity modifying agent having thixotropic behaviour is selected from a group consisting of hbydrogenated vegetable oil, colloidal silicon-di-oxide, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monostearate, gelatin, natural gums such as acacia, tragacanth, guar gum, xanthan gum or mixtures thereof. 8. A pharmaceutical composition for vaginal and rectal administration to prevent sexually transmitted disease (STDs) and acquire immunodeficiency syndrome (AIDS), having rapid dispersability in water to form a smooth, homogeneous, viscous and bioadhesive gel substantially as herein describe with reference to forgoing examples and drawings.

Full Text

A synergistic pharmaceutical composition for high molecular
weight polymer drugs
FIELD OF INVENTION
The present invention relates to a novel pharmaceutical composition useful for formulating a high molecular weight active(s) in a thixotropic, water swellable, and bioadhesive fill material for dispensing in gelatin and non-gelatin capsule dosage forms. The invention represents the art of formulating pharmaceutically active substances into more elegant medicaments/ The present invention is specifically designed for formulating high molecular weight microbicidal agents with intent of providing protection against sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS), by vaginal or rectal route. But the scope of invention is not limited to the use of microbicides only. The present invention can also be useful for formulating other high molecular weight compounds for vaginal or rectal administration.
The art of preparation lies in the fact that the thixotropic capsule fill material is easy to prepare and hydrophobic in nature but when comes in contact with water forms a smooth uniform gel with no visible physical separation of ingredients. The formulation behaves in a thixotropic manner, since it remains flowable at 37°C liquid, which aids in filling into capsules and solidifies at normal room temperature (20-25°C) thus helps in reducing leakage during storage.
BACKGROUND OF INVENTION
AIDS is a deadly disease causing millions of death each year. Various approaches are used to combat this disease. One such approach being explored extensively for prevention of AIDS is the use of microbicides. Development of microbicides gained impetus in past decade as these compounds not only prevent conception but also provide protection against AIDS. A number of polymeric materials such as sodium cellulose sulfate (Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Andrology 23, 426-438; US patent 6063773), polystyrene sulfonate (Zaneveld LJD, Waller DP, Anderson RA, Chany C,

Rcncher VVF, Feathergill K, Diao XH, Doncel GF, Herold B, Cooper M. 2002. Efficacy and safety ot a new vaginal contraceptive formulation containing high molecular weight poiy(sodium 4-styrencsulfonate). Biology of Reproduction 66, 886-894; US patent 6230182), polymethylene hydroquinone sulfonate (US patent 6239182), dextran sulfate (Baba M, Schols D, Pauwels R, Nakashima H, De Clercq E. 1990. Sulfated polysacchandes as potent inhibitors of HIV-induced syncytium formation: a new strategy towards AIDS chemotherapy. Journal of Acquired Immune Deficiency Syndrome 3, 493-9), sulfated polyvinyl alcohol (Baba M, Schols D, De Clercq E, Pauwels R, Nagy M, Gyorgyi-Edelenyi J, Low M, Gorog S. 1990. Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency vims replication and giant cell formation. Antimicrobial Agents and Chemotherapy 34, 134-138), and sulfated copolymer of acrylic acid with vinyl alcohol (PAYAS) (Baba M, Schols D, De Clercq E, Pauwels R, Nagy M, Gyorgyi-Edelenyi J, Low M, Gorog S. 1990. Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency vims replication and giant cell formation. Antimicrobial Agents and Chemotherapy 34, 134-138), etc. are being developed as microbicides.
The problems of rapid spread of sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS) are steadily growing. According to a report, about 340 million cases of curable STDs occurred throughout the world in the year 1999 (http://www.who.int; http://www.flii.org). According to "AIDS epidemic update -December 2001" by UNAIDS (http://www.unaids.org), 40 million people are living with AIDS and about 14000 new HIV infections occurred in a day in year 2001. About 3.97 million people are living with AIDS virus in India, (www.naco.nic.in). Worldwide, women face the greatest risk of acquiring human immunodeficiency virus (HIV) due to substantial mucosal exposure to seminal fluids, high prevalence of non-consensual sex, sex without condom use, and unknown, high-risk behaviors of their partners (NIAID Fact sheet, May 2001, http://www.niaid.nih.gov). Ratio of HIV positive women to men is increasing at a much faster rate. The number of women with HIV infection and AIDS has been increasing steadily worldwide. According to UNAID report, as of December 2001, 17.6 million women were living with HIV/AIDS worldwide, accounting for 47.3 percent of the 37.2 million adults living with HIV/AIDS (hup: www.unaids.or^). Despite taking all the precautions to

control its further spread, HIV positive females can't control its transmission to progeny. Looking at these facts, need of preventive measures for women is more as compared to men.
Attempts at developing vaccine against HIV have been unsuccessful so far, mainly because of the "dynamic" nature of virus. Drugs, which can cure the infection, although expensive, have shown a reasonable degree of success in extending the life span of those who are already infected. Attempts at limiting the spread of STDs and AIDS, through standard prevention tools such as use of condoms and behavioral modifications (monogamy and sex abstinence) have proven inadequate.
Under these conditions, a new category of prophylactic agents and formulations called "microbicides" are being developed with a hope, to control and put a stop to the rapid spread of STDs (Harrison, P.P. 2000 Microbicides: Forging scientific and political alliances. AIDS Patient Care and STDs 14, 199-205). These preparations are targeted for vaginal or rectal use and can be designed with and without contraceptive activity. They can also have a therapeutic benefit on sexually transmitted infections such as those caused by Candida sp., Chltimydia truchomatis, Neisseria gonorrhea, Trichomonas vaginalis etc. Vaginal and/or rectal microbicides can provide an alternative consumer friendly, protective methodology under the control of women to provide such protection.
The vagina, in addition to being a genital organ with functions related to conception, serves as potential route for daig administration. Mainly used for local action in the cervico-vaginal region, it has the potential for delivering drugs for systemic effects and uterine targeting. Traditionally vaginal cavity has been used for the delivery of locally acting drugs such as antibacterial, antifungal, antiprotozoal, antiviral, labor-inducing and spermicidal agents, prostaglandins and steroids. Several types of conventional vaginal dosage forms (VDFs) such as tablets, hard and soft gelatin capsules, creams, suppositories, pessaries, foams, ointments, gels, films, tampons, vaginal rings and douches are available. These suffer from various limitations such as leakage, messiness and low residence time, which contribute to poor subject or patient compliance. So there is a strong critical need to develop better dosage forms, which can meet the clinical as well as the user's requirements. Attempts are being made to develop novel vaginal drug delivery systems. Novel

developments such as bioadhesive systems and liposomes overcome some of the major limitations of conventional vaginal products.
As of now, only gels have been formulated using such compounds. CS and PSS are difficult to formulate in unit solid dosage forms as these are high molecular weight compounds and moreover form a matrix when come in contact with water thus interrupting the further ingress of water into the core resulting in poor dispersion of dosage form and release of medicament. There is a critical need to formulate these compounds into solid unit dosage forms in order to quantify the dose accurately so as to make it more patient compliant.
Sexually transmitted diseases (STDs) of bacterial origin that can be cured are the most common cause of illness worldwide. These can lead to long-term complications with serious social, heath and economic consequences. The estimated annual (1995) worldwide incidence of four major curable STDs, namely syphillis, gonorrhea (Neisseria gonorrhoeae), chlamydial infection and trichomoniasis, was about 330 million (Gerbase AC, Rowley JT, Heymann DHL et al. 1998. Global prevalence and incidence estimates of selected curable STDs. Sex. Transmitted Infections, 74, S12-S16). Apart from this AIDS is the major killer from the group of sexually transmitted disease of viral origin. There has thus heretofore been desired the development of preventive or curative agents from inexpensive, widely available resources, with broad antiviral and antibacterial activities. The development of safe and effective microbicides fulfilled the above necessities. Cellulose sulfate and polystyrene sulfonate are the two high molecular weight non-cytotoxic microbicidal compounds of polymeric nature with proven microbicidal activity. As per US patent 6063773 cellulose sulfate at concentration of 0.005% inhibits the binding of HIV to human cells in vitro, at concentration as low as 0.00001%, it inhibits infection of human cells by HSV in vitro, at a concentration of at least 0.01% can completely kill the bacteria N. gonorrhea and moreover it had no adverse effect on the normal vaginal flora (Lactobacillus gasseri). Moreover, the addition of cellulose sulfate in a concentration as low as 0.00001% is effective in inhibiting the infection of human cells by viral pathogens in vitro. The activity of cellulose sulfate is not affected by incorporating it in the present novel pharmaceutical composition as evident by the results of HI assay. Similarly according to US patent 6239182, PSS also inhibits the HIV virus with an IC
gonococci with an ICsn of about 3 ug/ml, and chlamydia multiplication at 1 ug/ml. Apart from the inhibiting sexually transmitted pathogens, both the compounds are contraceptive without significant cytotoxic effects. PSS inhibits a number of enzymes, including sperm hynluromdase reversihly vvhereas CS induces acrosomal loss in human spermatozoa and impedes the penetration by spermatozoa into the cervical mucus membrane /// viiro. The compounds have shown to have generally fewer side effects than conventional vaginal contraceptives (e.g., nonoxynol-9).
Different types of vehicles are reported for incorporating medicament in capsule dosage form. US patent 4695450 describes the utilization of anhydrous emulsion with an oil phase (o) and a hydrophilic phase (p) of water-soluble but anhydrous liquids, as a filler matrix for medicinal preparations in capsules. The anhydrous liquids were selected from polyethylene glycols of different molecular weights, dihydric alcohols, particularly propylene glycol, or tnhydric alcohols, particularly glycerol or mixtures thereof. But the use of such anhydrous agents results in brittleness of the shell as they have shown to withdraw water from the gelatin shell. The present invention does not contain any ingredient, which has adverse effect on gelatin shell. Moreover the present composition is thixotropic in nature as compared to the invention described above. This prevents the leakage of contents from capsule on storage.
According to US patents 4620974; 4777048 and 4832952, the use of liquid, non-solubilizing, hydrophilic lubricants markedly improves the dissolution rates of pharmaceutical composition contained in a hard gelatin capsule. They have used polyethylene glycols (in the molecular weight range of 200 to 900) along with active ingredient. There are number of reports, which states that polyethylene glycols (PEGs) are incompatible with hard gelatin capsule shell. PEGs take up water from the gelatin shell and thus make it brittle. The present invention contains all the ingredients, which are compatible with the gelatin shell and has been shown to be stable on accelerated stability conditions.
US patent 4795642 discloses a pharmaceutical composition comprising a gelatin capsule enclosing a solid matrix formed by the cation-assisted gellation of a liquid fill incorporating vegetable gum and a pharmaceutically-active compound. In this embodiment, a dispersion or solution containing active ingredient and a vegetable gum as a bulking agent

in capsule and than a gelling agent is added to this liquid filled capsules so as a matrix is formed in situ, which results in controlled release of medicaments after the rupture ol capsule. Such kind of in situ gellation is not preferable, as one cannot assess the changes happening inside the shell after addition of the gelling agent. Moreover this may result in large variability in release pattern with each dose as gelling takes place inside the sealed capsule. The properties of capsule shell may also be adversely affected by in situ gellation. The present invention does not involve such a complex and cumbersome procedure for preparing liquid/semisolid filled capsules and is very simple in design.
Liquid capsule formulations for vaginal use have been reported for incorporation of lactic acid bacteria dispersed in pharmaceutically acceptable carrier with viscosity range of 2000-4000 cPs. The vehicle selected contained oil and corn starch in order to preserve the integrity of the bacterial culture and to stabilize the formulation. Similarly, US patent 6365180 relates to the use of liquid or semi-solid compositions for filling into capsules for oral use. The invention dictates the use of active agents with at least one terminal ester group or chemically active moiety, which is removed or hydrolyzed in-situ. This patent makes an attempt to decrease the irritation potential of non-steroidal anti-inflammatory agents on incorporating it in liquid or semi-solid composition. Oral liquid composition stated in the above-mentioned patent involves pH modulation to avoid irritation whereas the present invention does not contain any ingredient, which has any reported irritation potential at the concentrations used in formulation for vaginal use. The present invention does not restrict itself to the use of moieties containing chemically active groups. Also, the present invention does not contain any solubilising agent or plasticizer.
Oil based drug delivery systems for hydrophobic drugs are described in US patent 5645856. US patent 6365181 reports the use of a thixotropic gelatin vehicle for filling into hard or soft gelatin capsules. The composition comprises of vegetable oil, viscosity modifier and surfactant. US patent 5738871 describes the use of hard gelatin capsules for delivery of fat soluble ingredients. The present invention not only incorporates some of the features of the above reported patents but also is especially suitable for incorporating high molecular weight compounds in specific. Moreover the present formulation is bioadhesive in nature and has excellent retention properties.

US patent 6165493 relates to administration of cellulose acetate phthalate (CAP) or hydroxypropyl methylcellulose phthalate (HPMCP), such as in micronized form, or a combination thereof, either alone or in combination with a pharmaceulically acceptable carrier or diluent for reducing the transmission of AIDS. According to inventors, the particularly preferred composition for these compounds is a micronized preparation containing CAP or micronized HPiMCP, a Poloxamer and distilled acetylated monoglycerides (a mixture of micronized CAP, poloxamer and acetylated monoglycerides is sold by the FMC Corporation under the trade name "AQUATERIC") suspended in glycerol. This formulation according to inventors can be dispensed in capsule dosage form. The present invention describes compositions containing high molecular weight compounds. The formulation in present invention does not contain glycerol, which may have an adverse effect on gelatin shell. In addition, the composition in present invention is bioadhesive in nature. It is more specifically designed to deliver these compounds topically in capsule dosage form in order to reduce costs and avoid possible disposal problems. The incorporation of high molecular weight compound in hard gelatin capsule is itself a challenge, which the present invention fulfills. It involves simple and efficient manufacturing process. Moreover the present invention discloses a formulation that possesses fast dispersion properties and is bioadhesive in nature in order to provide an intimate contact with vagina.

US patents 5514670, 5744155 and 5993846 relate to preparation of bioadhesive lipid-in-water emulsion for administering peptides along with absorption promoters. The high molecular weight peptides were incorporated into the inner lipid phase and lyophilized, which may be incorporated into capsules. On coming in contact with aqueous phase, it forms a continuous emulsion. The present invention is designed for incorporating high molecular weight compounds into capsules. At the same time, it does not involve any sophisticated and costly processes like lyophilization. The carrier phase of the present invention is thixotropic, bioadhesive and water swellable and is best suited for formulating high molecular weight compounds.
CS (US patent 6063773) and PSS (US patent 6239182) are non-cytotoxic contraceptive antimicrobial agents, currently under clinical stages of development. Phase 1 clinical studies for both CS gel (6% w/w) and PSS gel (10% w/w) have been successfully

completed. Both the compounds exhibit antimicrobial activity against sexually transmitted pathogens including HIV. Based on the in-vitro and animal experiments CS and PSS have proven to be effective and safe for use in reducing the risk of infection associated with STD causing pathogens and for contraception. The gels used in these prior arts are aqueous based gels. The present invention relates to vaginal capsules containing sodium cellulose sulfate (CS) or sodium polystyrene sulfonate (PSS) as active material, along with different excipient, which are non-aqueous in nature.
OBJECTS OF THE INVENTION
The main object of the invention was to formulate high molecular weight compounds in such a dosage form that is hydrophobic in nature, so that these do not swell during production, storage, handling, and administration. But as soon as the formulation is administered into vagina or rectum and comes in contact with vaginal secretions it should swell and form a smooth, homogenous, viscous and bioadhesive gel. At the same time, formulation should rapidly disperse, disintegrate and release the active moiety within few minutes of administration
Another object of the present invention is to provide a novel pharmaceutical composition useful for incorporating high molecular weight compounds, which obviates the drawbacks and possess desired characteristics as detailed above.
Another object of the present invention is to provide a elegant dosage form incorporating high molecular weight microbicidal agent for reducing the frequency of transmission and prevention of STDs and AIDS.
The other object of the present invention is to formulate high molecular weight compounds in a thixotropic medium that is liquid at high temperature and hence can be easily filled into capsules. On the other hand, it solidifies at room temperature, thus avoids the leakage during handling and storage.
Another object of the present invention is to provide a pharmaceutical composition that is hydrophobic in nature during formulation but should be totally water swellable when comes in contact with water.Another object of the present formulation is to provide a novel pharmaceutical
composition, which is bioadhesive in nature and retains well in vagina. Also the object of
the present formulation is to provide a useful pharmaceutical composition, which is simple
in design, involves less number of manufacturing steps and is easily amenable to mass
production.
Yet another object of the present invention is to provide a composition that can be useful for filling both in hard gelatin, soft gelatin and non-gelatin capsules.
Yet another object of the present invention is to provide a safe and relatively inexpensive method for vaginal and rectal delivery of drugs and pharmaceuticals.
Other objects, features, and advantages of the formulation will be more apparent to those versed in the dispensing art from reading the detailed description of the specification, taken in conjunction with the drawing figures and accompanying claims.
s i \ rr.vir.N r or 11 ir. INVENTION
A pharmaceutical composition for vaginal and rcclal administration to prevent sexua1ly transmitted disease (STDs) and acquire immunodeficiency syndrome (AIDS). Inning rapid dispersability in water to form a smooth, homogeneous, viscous and bioadhesive gel. the said composition comprising of a high molecular weight active ingredient in the range of 0.5 lo50 % w/w, hydrophobic vehicle in the range of 20 to 90% w/w. dispersing agent in the range of 0.1 to 10% w/w. a water swellable bioadhesive agent in the range of 0.5 to 45% w/w. and optionally a viscosity modifying agent in the range of 0.5 to 45.0% such as herein described.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition for vaginal or rectal administration to prevent sexually transmitted diseases (STDs) and Acquired Immunodeficiency Syndrome (AIDS).
BRIEF DESCRIPTION OF DRAWINGS AND TABLES
Figure 1. Thixotropic behavior of the CS capsule fill material measured using programmable Brookfield RVDV III + Programmable Rheometer (Brookfield Engineering, USA) and Rheocalc 2.1 software.
Figure 2. Thixotropic behavior of the PSS capsule fill material measured using programmable Brookfield RVDV III + Programmable Rheometer (Brookfield Engineering, USA) and Rheocalc 2.1 software.
Table 1. Physico-chemical characteristics of fill material for CS and PSS capsules
Table 2. Physico-chemical characteristics of CS and PSS capsules

Table 3. Bioadhesive strength and work of adhesion (average of 5 replicates ± standard deviation) of capsules as compared to other vaginal formulations currently underdevelopment or in market.
Table 4. Retention properties of capsules as compared to other vaginal formulations currently underdevelopment or in market.
DETAILED DESCRIPTION OF PRESENT INVENTION
Accordingly, the present invention provides a high molecular weight polymeric compounds (polystyrene sulfonate and cellulose sulfate) with proven microbicide activity are dispersed in an oil base containing a dispersing agent, bioadhesive agent and a viscosity enhancing/solidifying agent. The present invention discloses the composition and method for manufacturing of a thixotropic, water swellable, and bioadhesive formulation of high molecular weight active(s) for filling into capsule forms for vaginal or rectal administration. The composition is simple, easy to prepare, and involves very few steps for preparation. The capsules prepared show very fast and uniform dispersion in water and result in formation of a viscous bioadhesive gel, which is totally water-soluble. The capsule fill material and formulation was found to be fairly stable and consistent in performance after accelerated stability study.
An embodiment of the present invention provides a synergistic pharmaceutical composition for vaginal or rectal administration to prevent sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS), also having rapid dispersibility in water to form a smooth, homogeneous, viscous and bioadhesive gel, the said composition comprising:
w/w (%)
i) a high molecular weight active ingredient 0.5 to 50.0%
ii) a hydrophobic vehicle 20 to 90.0%
iii) a dispersing agent 0.1 to 10.0%
iv) a water swellable bioadhesive agent 0.5 to 45.0%
v) optionally, a viscosity modifying agent 0.5 to 45.0%

An embodiment of the present invention wherein a preferable synergistic composition comprises of:
w/w (%)
i) a high molecular weight active ingredient 8.0 to 30.0%
11) a hydrophobic vehicle 40.0 to 80.0%
in) a dispersing agent 2.0 to 8.0%
iv) a water swellable bioadhesive agent 10.0 to 35.0%
v) optionally, a viscosity modifying agent 10.0 to 35.0%
An embodiment of the present invention provides a composition having high molecular weight active ingredient which is microbicidal polyanionic polymer selected from phosphorylated hesperidins, sulfonated hesperidins, quercetin sulfate, polyvinyl alcohol sulfate, sulfated copolymer of acrylic acid with vinyl alcohol (PAVAS) polystyrene sulfonates, substituted benzene sulphonic acid formaldehyde co-polymers, sulphuric acid modified mandelic acids, cellulose aceate phthalate, sulfated cyclodextrins, dextrin sulfate, carrageenan, naphthalene sulfonate, polymethylene hydroquinone sulfonic acid, cellulose sulfate, dendrimers, neem oil fractions or derivatives, polystyrene hydantoin elastomer, povidone iodine, Lactobacillus spores and/or mixtures thereof.
An yet another embodiment of the present invention provides a high molecular weight active ingredient having molecular weight ranging from 5000 to 3 million Dalton, and above.
In still another embodiment provides a composition wherein an oily hydrophobic vehicle is selected from a group consisting of arachis oil, castor oil, cottonseed oil, maize (corn oil), olive oil, sesame oil, soyabean oil, sunflower oil, light liquid paraffin, safflower oil. theobroma oil, coconut oil, silicone oil, paraffin oil, hydrogenated vegetable oil, fish oil, primrose oil, mineral oil, vaseline oil, vegetable oils, animal oils, carbowaxes, glycol esters, i^lycerol esters, macrogol esters, cetosteryl alcohol, cetyl alcohol, lanolin, lanolin alcohols, sorbitan esters, fatty alcohols, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and/or mixtures thereof

Still yet another embodiment of present invention provides a composition, wherein the high molecular weight active ingredient used may be hydrophobia or hydrophilic in nature.
Still another embodiment of the present invention provides a composition, wherein the dispersing agent is selected from colloidal silicon-di-oxide, white soft paraffin, macrogol glycerides. poloxyethylene castor oil derivatives, mono, di and tri-glyceridcs (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and/or mixtures thereof.
Still yet another embodiment of the present invention, provides a composition wherein the bioadhesive agent is selected from a group consisting of acrylic acid polymers, gelatin, tragacanth, sodium carboxymethylcellulose, guar gum, propylene glycol alginate, bentonite, natural gums such as tragacanth, acacia, guargum, xanthan gum etc, alginates, chitosan, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, starches, pectins or mixtures thereof.
Still yet another embodiment of the present invention provides a composition, wherein the viscosity modifying agent having thixotropic behaviour is selected from hydrogenated vegetable oil, colloidal silicon-di-oxide, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monostearate, gelatin, natural gums such as acacia, tragacanth, guar gum, xanthan gum or mixtures thereof.
Still yet another embodiment of the present invention, the bioadhesive agent used can also act as a viscosity-modifying agent.
Still another embodiment of the present invention, the composition used can be incorporated into hard or soft gelatin or non-gelatin capsules.
Yet another embodiment of the present invention, the composition viscosity modifying agent with thixotropic property, remains liquid at normal filing temperature about WC and solidifies as the temperature drops down to ambient temperature of about 25°C is used.
Still yet another embodiment of the present invention, the composition undergoes fast dispersion, disintegration and the capsule fill material takes about nearly 2 min. to completely disperse after capsule shell disintegration.

Still another embodiment of the present invention, the composition having thixotropic till material forms a uniform smooth, homogenous, viscous and sticky gel by coming in contact with water.
Yet still another embodiment of the present invention, the composition possessing hioadhesive nature is retained well in vaginal cavity.
Yet still another embodiment of the present invention, the composition is obtained by simple manufacturing process involving mixing of ingredients with constant stirring in specific ratio at constant temperature.
Yet another embodiment of the present invention the composition involves minimum number of manufacturing steps.
Still another embodiment of the present invention the composition used is easily amenable to mass scale production.
Still another embodiment of the present invention the composition used is stable under extreme temperature and humid conditions.
Yet, still another embodiment of the present invention wherein the pharmaceutical composition retains a biological activity of the ingredients.
Yet still another embodiment of the present invention, consisting of a process for the preparation of synergistic pharmaceutical composition, the said process comprising steps of:
a) mixing a high molecular weight active ingredient, hydrophobic vehicle, dispersing
agent, water soluble bioadhesive agent, optionally with a viscocity modifying agent,
b) heating with stirring the mixture of step (a) up to 40 ° C to obtain a dispersion, and
c) filling the dispersion of step (b) into gelatin capsules
An embodiment of the present invention, pharmaceutical composition consists of a capsule incorporating high molecular weight compounds in an oily liquid base, a dispersing agent, a solidifying agent (hydrogenated vegetable oil), and a bioadhesive agent (a natural
gum).
Another embodiment of the present invention the retention behavior of capsule dispersion in simulated vaginal environment was studied using isolated sheep vaginal tissue after dispersing the one unit dose in 3 ml of saline. The results of the retention study depict that formulation retains well in vagina. The biological activity of the compounds in present invention is not affected even after 90 days of storage in accelerated stability conditions

(40°C and 75% RH) as evident by results of hyaluronidase inhibition (HI) assay. The cellulose sulphate as a compound is 97.16 percent active against hylauronidase at Img/ml concentration. This activity of cellulose sulphate in formulation is not altered even after storage at accelerated storage conditions (40°C and 75% RH) for a period of 90 days. Cellulose sulphate in formulation was found to be 104.62% active against hyaluronidase at 1.25 mg/ml, similar results were obtained for polystyrene sulfonate. The HI activities of 1 ing/ml solution of neat PSS and PSS capsule formulation after 90 days of accelerated stability studies were found to be 77.3 and 60.69% respectively.
These compounds neither upset the normal vaginal nor significantly disrupt the protective glycoprotein vaginal coating. As these are high molecular weight compounds, CS and PSS are not absorbed into systemic circulation. But because of their high molecular weight, these are usually difficult to formulate into any elegant solid unit dosage form.
An embodiment of the present invention, the present novel pharmaceutical composition formulates the said high molecular weight active in a hydrophobic media such that the formulation during storage or handling does not provide an appropriate media for high molecular weight compound to swell but as soon as this active comes in contact of water, the formulation starts swelling rapidly and forms a gel which when administered uniformly spread in vaginal cavity. The gel formed is bioadhesive in nature and retains well in vagina. The formulation is encapsulated in gelatin or non-gelatin shell. The use of hard gelatin capsule in vagina is slowly gaining impetus. The present invention contains the ingredients that are soluble, chemically and biologically compatible with active ingredients and are either GRAS listed and/or official in pharmacopoeias. The formulation is easily amenable to mass scale production and is flexible in terms of dose range.
An embodiment of the present invention, the present formulation is intended for administration into vaginal cavity. The formulation characteristics makes it best suitable for administration into vagina as it gels on dispersion after coming in contact with vaginal secretions as seen in in vitro experiments and thus forming a uniform layer all over, is sufficiently bioadhesive thus increasing the retention in the vaginal cavity, contains all the water soluble or miscible ingredients thus ensuring wash out of remnants out of vaginal cavitv, etc.

Yet another embodiment of the present invention, there are varieties of pharmaceutical compositions that use oil or hydrophobic materials to disperse the active ingredient. The liquid or seinisolid hydrophobic vehicles used in the present invention is selected Irom a group consisting of arachis oil, castor oil, cottonseed oil, maize (corn oil), olive oil, sesame oil, soyabean oil, sunflower oil, light liquid paraffin, safflower oil, theobroma oil, coconut oil, silicone oil, paraffin oil, hydrogenated vegetable oil, fish oil, primrose oil, mineral oil, vaseline oil, vegetable oils, animal oils, carbowaxes, glycol esters, glycerol esters, macrogol esters, cetosteryl alcohol, cetyl alcohol, lanolin, lanolin alcohols, sorbitan esters, fatty alcohols, mono, di and tri-glycerides (modified or unmodified) based on edible tats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstosteanc acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and mixtures thereof.
Still yet another embodiment of the present invention the materials that can be used as dispersing agents are selected from a group of colloidal silicon-di-oxide, white soft paraffin, macrogol glycerides, poloxyethylene castor oil derivatives, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and mixtures thereof.
Still another embodiment of the present invention, materials that can be used as bioadhesive or gel forming agents are selected from a group consisting of acrylic acid polymers, gelatin, tragacanth, sodium carboxymethylcellulose, guar gum, propylene glycol algmate, bentonite, natural gums such as tragacanth, acacia, guargum, xanthan gurn etc, algmates, chitosan, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, starches, pectins or mixtures thereof.
An embodiment of the present invention provides the use of viscosity modifying agent having thixotropic behaviour is selected from hydrogenated vegetable oil, Aerosil (colloidal silicon-di-oxide), diethylene glycol monostearate (Hydrine), ethylene glycol

monostearate (Monthvie), glyceryl monostearate (Pearlescent agent), gelatin, natural gums such as acacia, tragacanth, guar gum, xanthan gum or mixtures thereof.
In light of the above discussion, it will be readily appreciated by those versed in the subject art that a critical need exists for a novel pharmaceutical composition useful in delivering high molecular weight compounds, which is simple in design, involves less number of manufacturing steps, disperses rapidly and uniformly when administered, bioadhesive in nature and is easily amenable to mass production.
Capsules are the most flexible and versatile of all dosage forms. These require minimal excipients to formulate any compound. Capsules provide a means to accurately deliver the measured dose for rectal and vaginal application. Capsule also provides a protective shell for moisture sensitive compounds
The pharmaceutical composition is simple in design and is easy to manufacture. It involves only mixing and filling the dispersion in capsules. The present novel pharmaceutical composition represents a state-of-art to formulate capsules containing high molecular weight compounds that form a smooth, homogenous, viscous, and bioadhesive gel after dispersion in fluid.
During formulation development and production these compounds are difficult to handle as these form gel and block the nozzle of the delivering devices or pumps. Even when these are formulated as solid dosage forms, a gel layer is formed in contact with water, which prevents the further entry of water into solid core and thereby slowing down the further penetration of fluid and disintegration of the solid dosage form. For the compound to be delivered through vaginal route it should provide complete and fast dispersion of the actives ingredients. Incorporating high molecular weight compounds into rapidly dispersible formulations is again a challenge. The present invention overcomes this challenge.
The above composition is not a mere admixture. In fact, it is a synergistic composition having unexpected properties which are not anticipated or obvious to a person skilled in the art. The properties such as smoothness, longitivity, viscosity and bioadhesion arc excellent when compared with conventional compositions.

EXAMPLES
The following examples are given by the way of illustration and therefore should not he construed to limit the scope of the present invention.
Example 1:
One example of the present invention is the capsule containing PSS (PSS capsules) as high molecular weight agent. The composition is as follows:

(Table Removed)
Soyabean oil was weighed and to it added mixture of Labrafil and melted hydrogenated oil with continuous stirring at 40°C. To the above mixture xanthan gum was added followed by sodium polystyrene sulfonate. The uniform dispersion was than filled in hard gelatin capsule (size 00). Temperature was maintained to 40°C during preparation of fill material and filling into capsule shells.
Physico-chemical characteristics of the fill material and capsules are mentioned in Table 1 and Table 2 respectively.
Example 2:
Another example of the present invention is the capsule containing CS (CS capsules) as high molecular weight agent. The composition is as follows:
(Table Removed)
Sodium cellulose sulfate was mixed with soyabean oil for 10-15 min with continuous stirring. Xanthan gum was then added to the above dispersion followed by mixture of dispersing agent and solidifying agent The uniform dispersion was filled in hard gelatin capsules. Temperature was maintained to 40°C during processing.
Physico-chemical characteristics of the fill material and capsules are mentioned in Table 1 and Table 2 respectively.
Example 3: Process for the preparation of pharmaceutical composition
The pharmaceutical composition, in present invention, is manufactured by simple mixing the ingredients in a specific order while maintaining a constant temperature of 40°C. The actual process in case of sodium polystyrene sulfonate involves mixing of oil or hydrophobic vehicle with the said dispersing agent and melted hydrogenated vegetable oil. To the above mixture bioadhesive agent is added followed by the addition of above said active with constant stirring at 40°C. The uniformly formed dispersion is than filled in 00 size capsules. Liquid filling into hard gelatin capsule results in reducing the cross-contamination due to dust generation and has shown to reduce weight variation to about 1% as compared to powder filling in hard gelatin capsule. The liquid filling results in development of efficient and cost effective process. Apart from this, if the formulation is thixotropic in nature, as in present case, the material solidifies after filling and thus reduces the possibility of leakage from capsule shells. In case of sodium cellulose sulfate the manufacturing process involves the pre-mixing of cellulose sulfate in oil. Bioadhesive agent from the above said group is added to the above dispersion. To the thick mass, formed mixture of dispersing agent and thickening agent is added slowly with constant stirring. The temperature above 40°C and a constant rate of stirring should be maintained throughout the stirring.
Example 4: EVALUATION OF PERFORMANCE CHARACTERISTICS
The performance of present pharmaceutical invention was evaluated by conducting
following tests:
Visual examination
The formulated capsule fill material and capsules were visually examined for following parameters:
• Colour and Odor: These are characteristic subjective parameters for a given formulation.
Change in colour of the composition during storage is depictive of some chemical
change, if any.
• Consistency; Ideally capsule fill material should be liquid while filling and should
solidify after filling in order to reduce the leakage. When samples were removed from
stability chambers (4()°C and 75% RH), the consistency (i.e., liquid, semi-solid, solid) of
the formulation was recorded.
• Separation: Formulation was left undisturbed and was observed for separation of layers
if any at different time intervals.
• Lumps: The capsule fill material should ideally be free of any lumps as they block the
nozzle of the delivering device or pumps resulting in non-uniform filling. The
formulation was observed for any lump formation during batch preparation.
• Nature of formulation before and after dispersion in water was observed and recorded.
• Nature of gel formed after dispersion: The gel formed was observed for smoothness or
roughness, thick or thin, fibrous or non-fibrous nature, uniform or non-uniform,
stickiness etc.
• Any other physical change was also observed.
Settling
The capsule fill material and capsules were left undisturbed. If any settling is visible, that was reported as distinct or clear or no settling observed.
Kate of settling
If any settling is observed then the sample was heated so that it liquefies, kept undisturbed for half-an-hour and examined thoroughly. The rate of settling is ranked as very fast (settling within 5 min), fast (settling within 5-10 min), and slow (settling in more than 1 5 min).
Redispersibility
If case of settling of dispersion, the glass vial containing dispersion was shaken vigorously and redispersibility was recorded and ranked as fast (if redisperses within 5 min), slow (redisperses on shaking for 10 -15 min), and not redispersible (if no redispersion occurs after 15 min of vigorous shaking).
Dispersion Behavior
Measured about Igm of dispersion accurately and poured it in a glass beaker containing 10 ml of demineralised water at 37°C in a beaker placed on a magnetic stirrer with thermostatic control. The dispersion was stirred at a constant rpm. Following parameters were recorded as follows:
Time o f start of dispersion (min)
Time of completion of dispersion (min)
Dispersion behavior (uniform, not uniform, pattern of dispersion, any other factor)
Disintegration test
Disintegration time and behavior of capsules were evaluated with an in house developed in vitro method (Garg S, Vermani K, Gunjan, Waller DP, and Zaneveld LJD. 2002 Survey of vaginal formulations available in Indian market; physico-chemical characterization of selected products. International Journal of Pharmaceutical Medicine, in press). A defined volume of disintegrating fluid (10 ml) was taken in a cylindrical container fitted with a screen (BSS mesh # 10), maintained at 37°C and stirred at fixed rpm (300) with
the help of magnetic stirrer. Test capsules were placed above the screen and disintegration time recorded. A capsule was considered to disintegrate when all the contents came out of the partially dissolved capsule shell. Disintegration was studied using water as disintegrating fluid. Disintegration time and behavior were recorded. Different parameters recorded are:
••• Time at which capsule starts disintegrating (min) *J* Time of completion of disintegration (min) •I* Different visual observations during disintegration pH measurement of the formulation after dispersion
The pH of dispersion was measured at ambient temperature using a calibrated pH meter (Denver 220 pH conductivity meter, USA) fitted with a glass electrode. The pH meter was calibrated using certified buffers of pH 4, 7, and 10 (Fisher Scientific, USA).
Viscosity
The basic purpose of determining the viscosity of formulation after dispersion was to assess the in vivo behaviour of the formulation after capsule disintegration. Change in different rheological parameters during stability studies also help in predicting the changes occurring in formulation.
Viscosities of the fill dispersion (1 gm) diluted with water (20 ml) were measured using a Brookfield RVDV III+ Programmable Rheometer (Brookfield Engineering, USA) with coaxial cylinders (measuring spindle - SC4 21). For viscosity measurement, spindle was rotated at 20 rpm in case of example 1 (PSS capsules) and at 50 rpm in case of example 2 (CS capsules) for 1 minute. Viscosity measurements were done at 25°C. Viscosities of the dispersions of CS and PSS capsules in 20 ml of water (30°C) were compared to that of a marketed vaginal capsule formulation (Puregest, vaginal soft gelatin capsules containing progesterone, marketed by Sun Pharmaceutical Industries Ltd.). Viscosity was measured using Brookfield RVDV 111+ Programmable Rheometer with cylindrical spindle (SC4 21), rotated at 50 rpm for 1 minute.
Rheology
The aim of the present study was to assess the type of flow and thi.xotropic or antithixotropic nature of the formulation. Thixotropic property was studied by applying an increasing amount of shear to the formulation at a constant interval and than decreasing the shear at a constant interval in the same manner. Various parameters were recorded and graphs are plotted between shear stress Vs shear rate and viscosity Vs shear rate to assess the flow behaviour of the formulation. An ideal formulation should be uniform, non-lumpy and thi.xotropic for manufacturing (to allow filling into capsule shells) as well as storage to avoid leakage.
Viscosity was measured as a function of speed using a Brookfield RVDV III+ Programmable Rheometer with coaxial cylinders (measuring spindle - SC4-14), connected to a Pentium PC with Rheocalc Version 2.1 software. For rheological evaluation, shear rates (y) in the range of 48 to 96 s"1 were chosen and each one of them maintained for 30 sec at 25°C. Measurements were made of viscosity (r|) and shear stress (a) on increasing the shear rate (up curve) until the maximum rate was reached. Measurements of r| and a were then repeated by decreasing shear rate until the minimum value, providing the down curve.
Bioadhesion
The method to measure bioadhesion is based on the principle of measuring the force required to break the adhesive bond between a model membrane and test formulation. Isolated sheep vaginal mucosa was used as the model membrane (Institute animal ethics committee's permission was obtained for the use of isolated sheep vagina in the experiments). The test formulation is sandwiched between two model membranes fixed on flexible supports in the modified probes of texture analyzer for a sufficient period of time. After the adhesive bond has formed, the force required to separate the bond is measured as bioadhesive strength.
Bioadhesive strength of vaginal formulations was measured using a calibrated texture analyzer (Model TA-XT21, Stable Micro Systems, UK) equipped with a 5 kg load cell and modified probes. Data was acquired at a rate of 50 points per second, using fully integrated data acquisition and analysis software, i.e. Texture Expert Version 1.22. A
previously reported method (Vermani K, Garg S, Zaneveld, LJD. 2002, Assemblies for //; vitro measurement of bioadhesive strength and retention characteristics in simulated vaginal environment. Drug Development and Industrial Pharmacy, 28 (9), 1129-1142) was modified to measure bioadhesion using Texture analyzer.
The probes of equipment were modified so as to hold and provide a flexible support to sheep vaginal mucosa. Sheep (Ovis aries, non descriptive local breed) vaginal tissue was obtained immediately after the sacrifice of animals at a slaughterhouse. Vaginal tissue was cleaned, separated from the supporting muscular and connective tissues taking care to maintain the integrity of mucosa. The isolated tissue was frozen at -20°C till further use. Before experiments, sheep vaginal tissue was thawed in normal saline containing 0.1% w/v Sodium azide as preservative. After thawing, vaginal tube was incised longitudinally and tied to the modified probes with mucosal side exposed, using a thread.
For measuring bioadhesive strength, 0.5 gm of the dispersion (single unit dose of capsule dispersed in 3 ml normal saline), was applied in between the sheep vaginal mucosa on an area of 464 mm2. Membranes were kept in contact with the test sample for a period of 5 minutes under a constant force of 0.25 N in order to establish a proper contact between membrane and sample to allow the formation of adhesive bond. Force required to separate the two membranes (with dispersion in between) was measured by upper support of texture analyzer moving at a rate of 0.1 mm/sec. Maximum force required to break the adhesive bond was measured as bioadhesive strength and area under curve was measured as work of adhesion. All the formulations were evaluated using isolated sheep vaginal mucosa (n = 5) and mean bioadhesive strength and work of adhesion were determined.
Retention
The assembly to measure retention of a formulation in vaginal cavity is based on the principle of measuring the weight of formulation falling down under the influence of gravity, from an intact tubular portion of sheep vagina, suspended in vertical position and maintained at 27±1°C and 75±2% RH (Vermani K, Garg S, Zaneveld, LJD. 2002, Assemblies for in vitro measurement of bioadhesive strength and retention characteristics in
L^J vaginal environment, Drug Development and Industrial Pharmacy, 28 (9), 1129-1142). Dispersion of vaginal formulation, placed inside a vertically suspended excised sheep vaginal tube, was allowed to fall under the influence of gravity. The weight of formulation fell down, as a function of time, was recorded. The experiment was repeated with isolated sheep vaginal tissue placed at angle of 45 degrees to the horizontal.
Bioadhesive and retention properties of CS and PSS capsules were compared to that of Replens gel, (Columbia Laboratories, Aventura, FL, claimed to have bioadhesive properties), KY Jelly" (Advanced Care Products, Raritan, NJ; a frequently used marketed vaginal lubricant), Acidform gel (an investigational acid buffering bioadhesive vaginal gel formulation being developed at TOPCAD, Rush Presbyterian St Luke's Medical Center, Chicago, LfSA, presently in clinical trials), CS gel (6% w/w gel, presently in clinical trails) and PSS gel (10% w/w gel of PSS, presently in clinical trials).
Example 5: Hyaluronidase inhibition assay
The activity of the present actives against hyaluronidase is well established. The aim of present investigation is to see that whether the incorporation of said actives in the formulation affects its activity against hyaluronidase or not. Activity against hyaluronidase is quantified by measuring the extent of hyaluronic acid hydrolysis. This is measured by determining the concentration of N-acetylglucosamine-reactive material, resulting from enzyme action using a specrophotmetric method. If the amount formed in the reaction is less than control in the presence of a test material, this indicates a potential inhibition of the enzyme hyaluronidase, which performs the acid hydrolysis.
The method of assay is based on the principle originally described by Aronson and Davidson (Lysosomal hyaluronidase from rat liver. I. Preparation, Journal of Biological Chemistry 242 (3), 437-440). The colorimetric determination of N-acetylglucosamine at 545nm (Reissig JL, Strominger JL, Leloir LF. 1955. A modified colorimetric method fo rthe estimation of N-acetylamino sugars. Journal of Biological Chemistry, 217, 959-966) is used to quantify hyaluronic acid hydrolysis by bovine testicular hyaluronidase. The method has been modified such that the acetate buffer used in the hyaluronidase reaction mixture is neutralized with NaOH before the borate buffer is added. The spectral absorbance at 545 nm
is read, and compared to absorbance readings obtained with N-acetylglucosamine standards that have been reacted with p-dimethylaminobenzaldehyde. Main advantages of the Invention:
a) The present invention provides easy and economical process for the preparation of the
present pharmaceutical composition.
b) The pharmaceutical composition of the present invention is amenable for filling into
hard and soft gelatin and as well as non-gelatin capsules.
c) The pharmaceutical composition of the present invention has fewer side effects than
conventional vaginal contraceptives.
d) fhe pharmaceutical composition of the present invention neither upset the normal
vaginal nor significantly disrupts protective glyco protein vaginal coating.
e) Active high molecular ingredients of the present pharmaceutical composition are not
absorbed into systemic circulation.
REFERENCES:
1. Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC,
Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical
evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent.
J Andrology 23, 426-438
2. Baba M, Schols D, Pauwels R, Nakashima H, De Clercq E. 1990. Sulfated
polysaccharides as potent inhibitors of HIV-induced syncytium formation: a new
strategy towards AIDS chemotherapy. Journal of Acquired Immune Deficiency
Syndrome 3, 493-499
3. Baba M, Schols D, De Clercq E, Pauwels R, Nagy M, Gyorgyi-Edelenyi J, Low M,
Gorog S. 1990. Novel sulfated polymers as highly potent and selective inhibitors of
human immunodeficiency virus replication and giant cell formation. Antimicrobial
Agents and Chemotherapy 34, 134-138
4. Garg S, Vermani K, Gunjan, Waller DP, and Zaneveld LJD. 2002 Survey of vaginal
formulations available in Indian market; physico-chemical characterization of selected
products. International Journal of Pharmaceutical Medicine, in press.
5. Gerbase AC, Rowley JT, Heymann DHL et al. 1998. Global prevalence and incidence
estimates of selected curable STDs. Sex. Transmitted Infections, 74, S12-S16
6 Harrison, P.P. 2000 Microbicides: Forging scientific and political alliances. AIDS Patient Care and STDs 14, 199-205

7 Zaneveld LID, Waller DP, Anderson RA, Chany C, Rencher WF, Feathergill K, Diao
XH, Donccl GF, Herold B, Cooper M. 2002. Efficacy and safety of a new vaginal
contraceptive formulation containing high molecular weight poly( sodium 4-
styrenesulfonate). Biology of Reproduction 66, 886-894
US Patent Documents
(Table Removed)
Tabel 1. Physico-chemical characteristics of fill material for CS and PSS capsules
(Table Removed)
Table 2. Physico-chemical characteristics of CS and PSS capsules

(Table Removed)
Table 3. Bioadhesive strength and work of adhesion (average of 5 replicates + standard deviation) of capsules as compared to other vaginal formulations currently underdevelopment or in market.

(Table Removed)
Table 4. Retention properties of capsules as compared to other vaginal formulations currently underdevelopment or in market.

(Table Removed)
Retention was measured by suspending the isolated sheep vaginal tissue vertically
Retention was measured by placing the isolated sheep vaginal tissue inclined at an angle
of 45 decrees to the horizontal

We Claim:
1. A pharmaceutical composition for vaginal and rectal administration to prevent sexually transmitted disease (STDs) and acquire immunodeficiency syndrome (AIDS), having rapid dispersability in water to form a smooth, homogeneous, viscous and bioadhesive gel, the said composition comprising of a high molecular weight active ingredient in the range of 0.5 to 50% w/w, hydrophobic vehicle in the range of 20 to 90% w/w, dispersing agent in the range of 0.1 to 10% w/w, a water swellable bioadhesive agent in the range of 0.5 to 45% w/w, and optionally a viscosity modifying agent in the range of 0.5 to 45% such as herein described.
2. A pharmaceutical composition as claimed in claim 1, wherein the said composition preferably comprises a high molecular weight active ingredient in the range of 8 to 30% w/w, hydrophobic vehicle in the range of 40 to 80%> w/w, dispersing agent in the range of 2 to 8% w/w, a water swellable bioadhesive agent in the range of 10 to 35% w/w, and optionally a viscosity modifying agent in the range of 10 to 35%.
3. A pharmaceutical composition as claimed in claim 1, wherein the high molecular weight active ingredient is a microbicidal polyanionic polymer selected from a group consisting of phosphorylated hesperidins, sufonated hesperidins, quercetin sulfates, polyvinyl alcohol sulfate, sulfated copolymer of acrylic acid with vinyl alcohol (PAVAS), polysterene sulfonates, , substituted benzene sulphonic acid formaldehyde copolymers, sulphuric acid modified mandilic acid, cellulose acetate phthalate, sulfated cyclodextrin, dextrin sulfate, carrageenan, naphthalene sulfonate, polymethylene hydroquinone sulfonic acid, cellulose sulfate, dendrimers, neem oil fractions its or derivatrives, polystyrene hydantoin elastomer, povidine iodine, lactobassilus sporesand/or mixture thereof.

4. A pharmaceutical composition as claimed in claim 1, wherein an hydrophobic vehicle is selected from a group consisting of arachis oil, castor oil, cottonseed oil, maize (corn oil), olive oil, sesame oil, soyabean oil, sunflower oil, light liquid paraffin, safflower oil, theobroma oil, coconut oil, silicone oil, paraffin oil, hydrogenated vegetable oil, fish oil, primrose oil, mineral oil, Vaseline oils, animal oils, carbowaxes, glycol esters, glycerol esters, macrogol esters, cetosteryl alcohol, cetyl alcohol, lanolin, lanolin alcohols, sorbitan esters, fatty alcohols, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acids, and/ or mixtures thereof.
5. A pharmaceutical composition as claimed in claim 1, wherein the dispensing agent is selected from colloidal silicon-di-oxide, white soft paraffin, macrogol glycerides, poloxyethylene castor oil derivatives, mono, di and tri-glycerides (modified or unmodified) based on edible fats and fatty acids such as capric acid, caprylic acid, stearic acid, hydroxystearic acid, cstostearic acid, palmitic acid, linoleic acid, linolenic acid, succinic acid, oleic acid, adipic acid, behenic acid, lauric acid, mixtures of glycerides of more than one fatty acidsd, and/or mixtures thereof.
6. A pharmaceutical composition as claimed in claim 1, wherein the bioadhesive agent is selected from a group consisting of acrylic acid polymers, gelatin, tragacanth, sodium carboxymethylcellulosc, guar gum, propylene glycol alginate, bentonite, natural gums such as tragacanth, acacia, guargum, xanthan gum, alginates, chitosan, hydroxypropylmethyl

cellulose, hydroxypropyl cellulose, starches, pectins and/or mixtures thereof.
7. A pharmaceutical composition as claimed in claim 1, wherein the viscosity modifying agent having thixotropic behaviour is selected from a group consisting of hbydrogenated vegetable oil, colloidal silicon-di-oxide, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monostearate, gelatin, natural gums such as acacia, tragacanth, guar gum, xanthan gum or mixtures thereof.
8. A pharmaceutical composition for vaginal and rectal administration to prevent sexually transmitted disease (STDs) and acquire immunodeficiency syndrome (AIDS), having rapid dispersability in water to form a smooth, homogeneous, viscous and bioadhesive gel substantially as herein describe with reference to forgoing examples and drawings.

Documents:

735-DEL-2003-Abstract-(01-10-2008).pdf

735-DEL-2003-Abstract-(18-09-2008).pdf

735-del-2003-abstract.pdf

735-del-2003-assignment.pdf

735-DEL-2003-Claims-(01-10-2008).pdf

735-DEL-2003-Claims-(18-09-2008).pdf

735-del-2003-claims.pdf

735-del-2003-complete specification (granted).pdf

735-DEL-2003-Correspondence-Others-(18-09-2008).pdf

735-del-2003-correspondence-others.pdf

735-del-2003-correspondence-po.pdf

735-DEL-2003-Description (Complete)-(18-09-2008).pdf

735-del-2003-description (complete).pdf

735-DEL-2003-Drawings-(18-09-2008).pdf

735-DEL-2003-Form-1-(01-10-2008).pdf

735-DEL-2003-Form-1-(18-09-2008).pdf

735-DEL-2003-Form-1.pdf

735-del-2003-form-18.pdf

735-DEL-2003-Form-2-(01-10-2008).pdf

735-del-2003-form-2.pdf

735-del-2003-form-3.pdf

735-DEL-2003-Form-5-(18-09-2008).pdf

735-del-2003-form-5.pdf

735-DEL-2003-GPA-(18-09-2008).pdf

735-DEL-2003-Petition-137-(18-09-2008).pdf

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Patent Number

225919

Indian Patent Application Number

735/DEL/2003

PG Journal Number

01/2009

Publication Date

02-Jan-2009

Grant Date

03-Dec-2008

Date of Filing

28-May-2003

Name of Patentee

NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)

Applicant Address

SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SANJAY GARG	SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA.
2	KAVITA VERMANI	HOUSE NO. 36, JAGDISH NAGAR, JWALAPUR, HARDWAR, UTTARANCHAL 249407.
3	PRIYANKA ARORA	4-C SAKET ENCLAVE, PRATAP NAGAR, UDAIPUR, RAJASTHAN, INDIA.
4	GUNJAN KOHLI	B-25, KIRAN GARDEN, UTTAM NAGAR, UDAIPUR, NEW DELHI 110059, INDIA.
5	KANDRAPU RAGHUPATHI	DEVNOOR, DHARMSAGAR, WARRANGAL 506371, ANDHRA PRADESH, INDIA.
6	KASTUBH TAMBWEKAR	TAMBWEKAR NIWAS, 51, GOKHALE ROAD SOUTH, DADAR (WEST), MUMBAI-400 028, INDIA.

PCT International Classification Number

A61P 31/18

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA